Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease.

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Visser" }, { "@type": "Person", "name": "Matthew B. Buechler" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": "Fibroblasts, non-hematopoietic cells of mesenchymal origin, are tissue architects which regulate the topography of tissues, dictate tissue resident cell types, and drive fibrotic disease. Fibroblasts regulate the composition of the extracellular matrix (ECM), a 3-dimensional network of macromolecules that comprise the acellular milieu of tissues. Fibroblasts can directly and indirectly regulate immune responses by secreting ECM and ECM-bound molecules to shape tissue structure and influence organ function. In this review, we will highlight recent studies which elucidate the mechanisms by which fibroblast-derived ECM factors (e.g., collagens, fibrillar proteins) regulate ECM architecture and subsequent immune responses, with a focus on macrophages. As examples of fibroblast-derived ECM proteins, we examine Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Transforming Growth Factor-β-inducible protein (TGFBI), also known as BIGH3. We address the need for investigation into how diverse fibroblast populations coordinate immune responses by modulating ECM, including the fibroblast-ECM-immune axis and the precise molecular mediators and pathways which regulate these processes. Finally, we will outline how novel research identifying key regulators of ECM deposition is critical for therapeutic development for fibrotic diseases and cancer." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-119/v2", "name": "Enter the Matrix: Fibroblast-immune cell interactions shape extracellular..." } } ] } Home Browse Enter the Matrix: Fibroblast-immune cell interactions shape extracellular... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Altieri A, Visser GV and Buechler MB. Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.12688/f1000research.143506.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Revised Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] Previously titled: Enter the Matrix: Fibroblast-immune interactions shape ECM deposition in health and disease. Anthony Altieri 1 , Grace V. Visser 1 , Matthew B. Buechler https://orcid.org/0000-0003-1902-622X 1 Anthony Altieri 1 , Grace V. Visser 1 , Matthew B. Buechler https://orcid.org/0000-0003-1902-622X 1 PUBLISHED 05 Dec 2024 Author details Author details 1 Immunology, University of Toronto, Toronto, Ontario, Canada Anthony Altieri Roles: Writing – Original Draft Preparation, Writing – Review & Editing Grace V. Visser Roles: Writing – Original Draft Preparation, Writing – Review & Editing Matthew B. Buechler Roles: Conceptualization, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Cell & Molecular Biology gateway. This article is included in the Advances in Fibroblast Research collection. Abstract Fibroblasts, non-hematopoietic cells of mesenchymal origin, are tissue architects which regulate the topography of tissues, dictate tissue resident cell types, and drive fibrotic disease. Fibroblasts regulate the composition of the extracellular matrix (ECM), a 3-dimensional network of macromolecules that comprise the acellular milieu of tissues. Fibroblasts can directly and indirectly regulate immune responses by secreting ECM and ECM-bound molecules to shape tissue structure and influence organ function. In this review, we will highlight recent studies which elucidate the mechanisms by which fibroblast-derived ECM factors (e.g., collagens, fibrillar proteins) regulate ECM architecture and subsequent immune responses, with a focus on macrophages. As examples of fibroblast-derived ECM proteins, we examine Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Transforming Growth Factor-β-inducible protein (TGFBI), also known as BIGH3. We address the need for investigation into how diverse fibroblast populations coordinate immune responses by modulating ECM, including the fibroblast-ECM-immune axis and the precise molecular mediators and pathways which regulate these processes. Finally, we will outline how novel research identifying key regulators of ECM deposition is critical for therapeutic development for fibrotic diseases and cancer. READ ALL READ LESS Keywords Fibroblasts, Fibroblast heterogeneity, Extracellular Matrix (ECM), Immunology, Macrophages, BigH3, Cthrc1 Corresponding Author(s) Matthew B. Buechler ( [email protected] ) Close Corresponding author: Matthew B. Buechler Competing interests: No competing interests were disclosed. Grant information: This study was funded by Canadian Institutes of Health Research (471606) and Medicine by Design. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Altieri A et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Altieri A, Visser GV and Buechler MB. Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.12688/f1000research.143506.2 ) First published: 19 Feb 2024, 13 :119 ( https://doi.org/10.12688/f1000research.143506.1 ) Latest published: 05 Dec 2024, 13 :119 ( https://doi.org/10.12688/f1000research.143506.2 ) Revised Amendments from Version 1 Based on the reviewers’ comments, the authors have updated the text and figures providing additional written information regarding the relevance of fibroblast heterogeneity in tissue architecture and disease states; the contribution of metabolic factors to immune cell – fibroblast crosstalk; and diverse fibroblast contributions to wound healing. Moreover, additional information has been provided related to BIGH3, including its similarities to Periostin; the tissue specific functions of BIGH3; and the alternative mechanisms by which it regulates collagen deposition. Aligned with this, all figures and figure legends have been modified to reflect the updated text. These changes include the addition of fibroblast-derived metabolic factors to Figure 1; the representation of different fibroblast subsets and effect modifiers in Figure 2; the addition of alternative mechanisms for BIGH3-mediated regulation of ECM turnover in Figure 3; and a new graphical representation in Figure 4. Based on the reviewers’ comments, the authors have updated the text and figures providing additional written information regarding the relevance of fibroblast heterogeneity in tissue architecture and disease states; the contribution of metabolic factors to immune cell – fibroblast crosstalk; and diverse fibroblast contributions to wound healing. Moreover, additional information has been provided related to BIGH3, including its similarities to Periostin; the tissue specific functions of BIGH3; and the alternative mechanisms by which it regulates collagen deposition. Aligned with this, all figures and figure legends have been modified to reflect the updated text. These changes include the addition of fibroblast-derived metabolic factors to Figure 1; the representation of different fibroblast subsets and effect modifiers in Figure 2; the addition of alternative mechanisms for BIGH3-mediated regulation of ECM turnover in Figure 3; and a new graphical representation in Figure 4. To read any peer review reports and author responses for this article, follow the "read" links in the Open Peer Review table. READ REVIEWER RESPONSES Introduction Fibroblasts orchestrate ECM deposition in steady state and disease: Fibroblasts are non-hematopoietic mesenchymal stromal cells which are found in all tissues, regulate tissue structure, and influence the phenotype and localization of tissue resident cell types. 1 – 3 As a result, fibroblasts play a critical role in tissue homeostasis and tissue repair. Fibroblasts accomplish these functions in part by producing and secreting extracellular matrix (ECM) proteins, which alter the structure and composition of the composite tissue ECM. 3 Here, the ECM refers to the diverse network of proteins that generates the three-dimensional structure of tissues. 4 – 6 In addition, fibroblasts secrete a variety of molecules, including cytokines and chemokines, which can bind the ECM to influence immune cell function and recruitment. 2 , 3 , 7 Under homeostatic conditions, fibroblast-derived ECM proteins provide essential support to resident cells and tissues. However, dysregulation of the ECM can contribute to pathogenic outcomes, including fibrosis. When tissues are injured, local tissue fibroblasts become activated and increase their contractility, secretion of inflammatory mediators, and synthesis of ECM components. 3 , 8 These changes initiate the wound healing response. 1 When damage is limited and non-repetitive, wound healing is efficient, a transient increase in the deposition of ECM components transpires to facilitate the restoration of functional tissue architecture. 2 However, when injury is repetitive or severe such as in chronic inflammatory diseases, ECM components continue to accumulate, which can lead to structural alterations of the ECM, disruption of tissue architecture, organ dysfunction, and ultimately, organ failure. 1 , 4 In these situations, fibroblasts produce excessive ECM, and changes to the fibrillar collagen network result in pathological tissue stiffness, loss of mechanical compliance, and loss of tissue function. 2 As a result, fibrotic disease affects almost all organ systems and is a contributing factor in 45% of all deaths in high income countries. 8 , 9 Therefore, an appreciation of the interconnectivity between fibroblasts, the ECM, and immune cells is required to understand the causality of fibrotic disease. 3 Here we integrate the current understanding of the fibroblast-ECM-immune axis and review the evidence supporting current models defining fibroblast-immune interactions. These studies serve as the basis for future exploration into immune cell regulation by fibroblast-derived ECM molecules. ECM form & function: The ECM is a dynamic 3-dimensional network of more than 300 different core proteins and matrix-modifying enzymes (often referred to as the matrisome). 5 , 6 , 10 These components are produced and assembled by fibroblasts and may either be long lived or transient, making ECM dynamic and sensitive to local and systemic changes. 2 Components of the ECM include collagens, proteoglycans (PGs), glycosaminoglycans (GAGs), elastin and elastic fibers, laminins, fibronectin, mucus and other proteins and glycoproteins, such as matricellular proteins. 2 , 4 , 5 The diversity of proteins in these functional groups is immense. For example, there are approximately 28 types of collagens, molecules which provide structural support to tissues. These components may also combine for additional diversity. For example, fibril-forming collagens have abilities to form covalent cross-links and create matrix structures and include collagens I, II, III, V, and XI. These ECM components have a variety of disparate functions while providing architectural support to tissues. For example, collagens provide tissue strength and resilience, PGs form hydrated gels which cushion tissues, and mucus protects barrier surfaces. 2 , 4 In addition, these components contribute to fundamental processes for tissue development, including cell proliferation, survival, migration, differentiation, autophagy, and angiogenesis. 4 These concepts have been reviewed extensively elsewhere. 4 There are a variety of other fibroblast-derived molecules and enzymes which modify ECM structure and regulate their degradation, such as matrix metalloproteinases (MMPs). 1 Moreover, fibroblasts produce molecules which bind ECM components to alter the composition and function of ECM-resident cells. For example, fibroblasts produce and secrete cytokines, chemokines, and growth factors, which are an implicit part of immune cell regulation. 2 It is also notable that immune cells are often connected to the unique matrix surrounding them, and every cell to varying degrees is coated in a glycocalyx, a complex network of sugar rich molecules either free or bound to proteins and/or lipids. 2 , 11 As a result, the ECM regulates the signaling, functions, properties, and morphology of residing immune cells in addition to providing structural support for tissues. 4 These properties may be altered in a tissue-specific manner. 3 Specific ECM phenotypes configure the different tissues, including epithelial, muscle, connective, and more to meet the requirements for optimal tissue function. 4 , 12 Here, the prevalence of different, tissue-specific heterogeneous fibroblast subsets with unique gene expression signatures can further alter the ECM and therefore tissue characteristics. 13 Aligned with this, Muhl et al. used a scRNA-seq approach to reveal that fibroblast heterogeneity in ECM and matrisome production was a function of tissue specific differences in the heart, skeletal muscle, colon, and bladder. 14 Finally, fibroblasts have unique functions depending on disease states. Fibroblasts that become activated due to repeated injury and chronic inflammation are typically referred to as myofibroblasts and have altered gene expression profiles that drive fibrotic disease. For example, Korunsky et al. performed cross-disease single cell RNA sequencing study of human inflammatory fibroblasts and demonstrated that two different myofibroblast subsets were preserved across Sjogren’s syndrome, interstitial lung disease, ulcerative colitis, and rheumatoid arthritis. Here, CXCL10+CCL19+ inflammatory fibroblasts localized with IFN-, TNF- and IL-1- producing T cells, whereas SPARC+COL3A1+ fibroblasts colocalized to a perivascular niche with elevated levels of TGF- and Notch ligands. 15 Below, we highlight critical immune-facing functions of fibroblast- and myofibroblast-derived ECM components in steady-state and disease. 5 ECM-based regulation of fibroblast-macrophage interactions Fibroblasts produce cytokines and chemokines which bind the ECM and are critical for immune cell recruitment and function in steady-state and disease 2 , 16 ( Figure 1 ). For example, multiple in vitro and tissue-restricted in vivo studies have demonstrated that a relationship exists between fibroblasts and macrophages, an innate immune cell which orchestrates long-lived adaptive immune responses through phagocytosis, antigen presentation, and immunological mediator secretion. 16 Fibroblasts and macrophages are found in almost all tissues and multiple studies indicate that fibroblast-derived CSF1, which can decorate the ECM, is a critical factor for macrophage survival. Using in vitro studies, Zhou et al. demonstrated that macrophages and fibroblasts form stable cell circuits that are resistant to perturbations and that cell-to-cell contact increased cell circuit survival because of local exchange of growth factors, including CSF1. 17 In addition, in vivo studies have demonstrated that fibroblastic reticular cells (FRC) are required to establish the lymph node (LN) macrophage niche. D’Rozario et al. demonstrated that genetic ablation of FRC using a genetic tool in which Chemokine (C-C motif ) ligand 19 ( Ccl19 )-expressing cells could be depleted using diphtheria toxin resulted in rapid loss of monocytes and macrophages from LN in two separate in vivo models. 18 Moreover, single-cell RNA sequencing (scRNA-seq) of murine brachial lymph nodes revealed that FRC subsets broadly expressed master macrophage regulator CSF1 and functional assays containing purified FRC and monocytes showed that CSF1R signaling was sufficient for macrophage survival. 18 Comparative analysis demonstrated these effects were conserved between mice and humans. 18 Figure 1. Fibroblast influence macrophage accumulation by altering the composition of the ECM. Fibroblasts use several mechanisms to recruit macrophages to the ECM. Fibroblast-derived cytokines and chemokines bind the ECM and enhance accumulation of ECM-associated macrophages. Fibroblast contraction remodels collagen fibers to enhance macrophage recruitment. Metabolic factors alter macrophage population dynamics and function. Fibroblasts secrete MMPs to cleave ECM- and ECM bound proteins to enhance macrophage accumulation in the ECM. Monocytes, which can give rise to macrophages, have also been shown to require stromal cell derived CSF1. Emoto et al. demonstrated that CSF1 produced by sinusoidal endothelial cells was required for the survival of Ly6C- monocytes. Conversely, CSF1 produced by both endothelial and Lepr + perivascular stromal cells were required for the survival of Ly6C hi monocytes. 19 Taken together, these studies demonstrated that macrophage survival in specific tissues is regulated by stromal-derived CSF1. While all fibroblasts can generate CSF1, tissue-specific fibroblast subsets do exhibit different levels of CSF1 mRNA, 20 so additional studies are required to delineate which subsets are critical for macrophage homeostasis. Further investigation is required to determine the functional role of macrophages sustained by fibroblast-derived CSF1 in steady-state and disease. Previous work by Zhu et al. has demonstrated that a pharmacologically induced CSF1 blockade in mouse pancreatic tumour models results in increased antigen presentation and productive antitumour T cell responses. 21 Despite this, the precise contribution of fibroblast-derived CSF1 in antitumour immunity is not well understood. Furthermore, the functional contributions of these macrophages in chronic inflammation and cancer also require subsequent study. In addition to cytokines, activated fibroblasts, including myofibroblasts, produce ECM-binding macrophage chemoattractants indicating that fibroblasts are capable of recruiting monocytes and macrophages during injury, infection, and inflammation. 22 , 23 For example, the bacterial ligand lipopolysaccharide (LPS), which activates toll-like receptor (TLR)4, has been shown to enhance expression of macrophage chemoattractants Ccl2 and Ccl4 in myofibroblast progenitor cells in a mouse model of liver fibrosis. 22 As LPS-mediated TLR4 activation occurs widely in anti-bacterial immunity, this suggests that fibroblasts can respond to pathogen-associated molecular patterns (PAMP) to recruit immune cell subsets, including macrophages, in a variety of anti-infective contexts. However, the role of fibroblast-mediated macrophage recruitment in additional anti-infective immune responses, as well as chronic inflammation, requires future investigation. Fibroblasts influence macrophage migration through mechanical cues. Previous studies have also demonstrated that fibroblasts can influence macrophage dynamics by regulating the physical mechanics of the ECM ( Figure 1 ). Hinz and colleagues showed that contractile myofibroblasts drive mechanical cues through local remodeling of collagen fibers resulting in increased macrophage migration directly towards myofibroblasts using 3D collagen gels in vitro. 24 Migration occurred independently of chemotaxis and required macrophage-mediated attachment to collagen via the α2β1 integrin and stretch-sensitive ion channels. 24 Similar observations have been described in several fibroblast-like cells, 25 – 27 indicating the importance of these biomechanical mechanisms for cell communication and movement across tissues. Fibroblast-derived matrix metalloproteinases degrade ECM proteins to enhance macrophage recruitment. Matrix metalloproteinases (MMPs) are a family of enzymes which degrade ECM proteins. These enzymes are either secreted or attached to cell surfaces, confining their activity to membranes, secreted proteins, or proteins within the extracellular space. 28 MMPs have a complex role in regulating inflammation by acting on a multitude of immunological mediators, including antimicrobial host defense peptides, cytokines, chemokines, and ECM proteins as reviewed in detail here. 28 In addition, matrix metalloproteinases are enhanced in stromal cells, including fibroblasts, in response to pro-inflammatory cytokines. 29 – 31 As a result, modulation of the ECM during inflammation alters immune cell migration and ECM resident cell types, including macrophages ( Figure 1 ). For example, Shubayev et al. demonstrated that TNF-α-mediated MMP9 (also known as gelatinase B) production enhances macrophage recruitment in a model of peripheral nerve injury. 32 Gong et al. demonstrated that mice deficient for the ECM-bound protease plasminogen (Plg) had decreased trans-ECM macrophage migration and decreased MMP9 activation. 33 In addition, the authors demonstrated that MMP9 administration to Plg deficient mice resulted in increased macrophage accumulation in the ECM, 33 suggesting that Plg activates MMP9 to increase ECM resident macrophages. Moreover, Tan et al. demonstrated that MMP9 can also cleave the ECM protein osteopontin (OPN) to enhance macrophage recruitment in a mouse model of renal fibrosis. 34 Despite this, additional studies are required to understand how MMP-mediated degradation of other ECM components alters immune cell recruitment and fibrotic disease development. In addition to cytokines, mechanical cues, and enzymatic means, fibroblast can regulate immune cell regulation through metabolic cues. Previous studies have demonstrated that metabolic factors are required for continuing collagen deposition during fibrotic disease. Schworer et al. demonstrated that the metabolic enzyme pyruvate carboxylase (PC) is required anaplerosis in tumour-associated fibroblasts for continuing collagen deposition in the glutamine and glucose scare tumour microenvironment (TME). 35 Kay et al. also demonstrated that collagen deposition requires de novo synthesis of the amino acid proline, a major component of multiple collagens, from glutamine, by the enzyme pyrroline-5-carboxylate reductase 1 (PYCR1). 36 Despite these findings, the impact that this had on immune cell, and specifically macrophage, infiltration into the TME was not investigated. To this end, some studies have investigated the interplay between metabolic factors and macrophage accumulation in various tissues. Buechler et al. demonstrated that Wt1 + stromal cells produce retinoic acid (RA) to maintain a population of GATA6+ Large Cavity Macrophages (LCM) in the peritoneal, pleural, and pericardial spaces. 37 Similarly, Pucino et al. demonstrated that physiological concentrations of lactate in RA joints induces the IL-6 production in fibroblasts, 38 which may enhance the differentiation of monocytes into macrophages. 39 Taken together, these studies provide the rationale for future investigations on how metabolic factors alter the relationship between fibroblasts, ECM deposition, and macrophage accumulation. Immune-induced fibroblast heterogeneity dictates ECM deposition In addition to fibroblast-derived components, immune-derived cytokines and growth factors play a critical role in fibrosis and fibrotic diseases by altering fibroblast heterogeneity and therefore ECM deposition. Below, we highlight the relationship between inflammation, fibroblast heterogeneity, and ECM deposition ( Figure 2 ). Moreover, we outline the role that modulators of growth factor signaling play in shaping ECM deposition and subsequent fibrotic disease. Figure 2. Heterogeneous fibroblast subsets alter the ECM. Fibroblasts become activated in response to cytokines and growth factors. These immune-derived signals are further modified by factors such as time, spatiality, repetitive injury, and chronic inflammation to adopt specific phenotypes, including profibrotic or regenerative, which alter the production of ECM components. As a result, these heterogeneous fibroblast subsets can alter the physical properties of the ECM, as well as ECM-resident cells. In addition, fibroblasts produce molecules, including TGFBI/BIGH3 and CTHRC1 which play multifaceted roles in regulating fibroblast-mediated ECM deposition. ECM composition is regulated by diverse fibroblast subsets in health and disease. Here, pro-inflammatory cytokines, growth factors, and other ECM proteins can convert fibroblasts into myofibroblasts. 40 Broadly, fibroblasts found in unperturbed tissues, myofibroblasts typically exhibit increased expression of contractile protein genes, such as alpha smooth muscle actin ( Acta2 ) 41 as well as other of ECM proteins. 42 However, the full extent of fibroblast heterogeneity is much more extensive. Multiple single-cell -omics studies have demonstrated that fibroblasts are highly heterogeneous, especially within wounds. Guerrero-Juarez et al. highlighted the dynamic nature of fibroblast identities during wound healing and defined 12 different clusters/subtypes of fibroblasts that both coexisted within wounds and/or represented consecutive differentiation states with disparate expression profiles, including contractile and regenerative fibroblasts. 43 Aligned with this Phan et al. also performed single-cell transcriptomic analysis in previously published wound-induced hair follicle neogenesis (WIHN) datasets and identified a population of regenerative fibroblasts marked by the expression of the retinoic acid binding protein Crabp1 which shared a gene signature with murine papillary fibroblast lineages which are required for hair follicle homeostasis. 44 , 45 Similarly, Foster et al. used an integrated spatial multi-omics studies approach and highlighted the coexistence of different functional fibroblast subsets across space and time, including activated, responder, proliferator, remodeling, and mechanofibrotic fibroblasts which expressed Col1a1 , Acta2 , and Pdgfra . 46 Identification of these subsets in wound healing is also translatable to identifying pathogenic fibroblast subsets across different disease states, such as cancer. For example, Wietecha et al. developed an in silico pipeline to identify genes and pathways to perform comparative analysis between kinetic healing and cancer transcriptomes. This comparison resulted in the identification of CAF in the inner tumour stroma similar to skin fibroblasts found in early wounds, which express collagen related genes, including Postn , Tnc , and Col12a1 regulated by the transcription factor RUNX2. 47 These CAF were associated with increased severity in skin cancer, suggesting that understanding fibroblast heterogeneity and trajectories in wound healing may yield insights in other disease states. The diversity of and trajectory of fibroblast subsets may be a function of immune-derived signals. Transcriptomic studies have demonstrated that macrophage:fibroblast crosstalk occurs in wound healing. Hu et al. performed in silico pathway analysis in a mouse model of wound healing to identify the macrophage-derived Oncostatin-M (OSM) pathway as a critical modulator of fibroblast function in early stages of wounds healing. Subsequent in vitro analysis demonstrated that OSM enhances the expression of Serpinb2 , Serpine1 , and Bnip3 in fibroblasts. 48 Similar findings have been observed in lineage tracing studies. Building on previous experiments in mice which demonstrated that embryonic mesenchymal precursors expressing Engrailed ( En1 ) or Delta-like homolog 1 ( Dlk/Pref1 ) generate skin fibroblast and adipocyte lineages, Shook et al. demonstrated that the predominant population of ECM-producing myofibroblasts in the skin are adipocyte precursor cells (AP) derived from En1 -lineage traced fibroblasts. 49 In addition, this study demonstrated that wound bed myofibroblasts upregulated Acta2 and Col1a1 mRNA expression compared to fibroblast populations from uninjured skin. 49 Further, the authors compared the transcriptional profiles of 2 major populations of fibrotic mesenchymal cells that are enriched in skin wound beds: APs and CD29 high cells. APs had greater expression of ECM components/regulators including collagens Col5a2 , Col14a1 , as well as matrix metalloproteinases Mmp2 , Mmp3 , Mmp23 , Mmp27 . Conversely, CD29 high fibroblasts expressed elevated levels of Col6a3 , Col7a , Mmp13 , and Tnc . Moreover, platelet-derived growth factor C ( Pdgfc ) secreted by CD301b-expressing macrophage triggered the proliferation of APs, but not other myofibroblasts, highlighting the role of immune-derived growth factors in shaping fibroblast heterogeneity. Similar findings related to macrophage:fibroblast crosstalk have been observed in human studies. For example, Ng et al. demonstrated that MERTK+ macrophages inhibit the inflammatory phenotype of capsular fibroblasts via integrin-mediated extracellular matrix remodeling. 50 However, more human studies are required to determine the role of macrophages in altering wound healing and other disease contexts. In addition to altering wound healing by secreted soluble cytokines and growth factors, macrophages promote the differentiation of regenerative or fibrotic fibroblast subsets by phagocytosing transcription factors. Gay et al. demonstrated that late stage wound macrophages phagocytize Wnt inhibitor SFRP4 to promote fibrogenesis over regeneration. 51 Taken together, these studies highlight the diverse contributions of fibroblast subsets to wound healing by way of ECM deposition. Although select studies have elucidated how cytokines or growth factors alter fibroblast-mediated ECM deposition and therefore their respective fibrotic or regenerative phenotypes future work is required to define the precise mechanisms by which ECM deposition is regulated. Transforming growth factor beta (TGF-β) is a major immune-derived growth factor which drives the expression of myofibroblast-associated genes. TGF-β is produced by a variety of cells, including macrophages, under inflammatory conditions and drives myofibroblast activation. 16 In the canonical TGF-β pathway, Latent TGF-β is activated by a v integrins in the ECM and binds to TGF-β receptor 2 on fibroblasts to drive the activation of intracellular kinases, including SMAD2/3, co-SMAD, and SMAD4 to upregulate ECM and myofibroblast-associated genes, such as C ol1a1, Fn1 and Acta2 . 52 , 53 In addition, TGF-β can also signal through non-canonical signaling pathways and activate all three mitogen-activated protein kinase (MAPK) pathways and proteins, including extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun-N-terminal kinase (JNK). 52 TGF-β-mediated signaling through these pathways may occur in either a Smad-dependent or -independent fashion. 52 TGF-β also activates Rho GTPase signaling and the PI3 kinase/Akt pathway. 52 As TGF-β is crucial for myofibroblast development and ECM production, modulators of TGF-β-signaling may be co-factors that affect myofibroblast phenotypes and ECM production from these cells. We define co-factors as proteins that are required for optimal signaling of another protein, such as TGF-β. We propose that identifying co-factors to TGF-β-driven myofibroblast activation and pro-fibrotic ECM deposition may represent potential targets for therapeutic development. In the following sections, we highlight two potential immune-derived co-factor candidates: CTHRC1 and BIGH3. Fibroblast-derived CTHRC1 as a regulator of ECM deposition Collagen triple helix repeat containing 1 ( CTHRC1) , a secreted ECM protein, has recently been identified as a critical modulator of ECM protein modulation and wound healing. 54 , 55 Human CTHRC1 contains a N-terminal 30 amino acid hydrophobic signal peptide secretory domain, a short collagen triple helix repeat (CTHR) domain consisting of 12 repeats of the Gly-X-Y motif, and a highly conserved C-terminal domain with similar structure of the globular C1q domain of Collagen VIII. 56 , 57 CTHRC1 is expressed in macrophages, myofibroblasts, endothelial cells as well as mesenchymal-derived cells 58 and as a result, CTHRC1 expression occurs in multiple tissues, including the bone, 59 the lung, 60 and tumours. 61 Previous studies suggest that CTHRC1 modulates TGF-β signaling ( Figure 3A ). For example, Cthrc1 modulates TGF-β signaling by promoting the degradation of canonical signaling intermediates, including Smad2/3, and has been suggested to influence Wnt and b-integrin signaling to affect cancer cell proliferation and metastasis. 58 Guo et al. showed that Cthrc1 modulated β-integrin signaling by enhancing phosphorylation of Focal adhesion kinase (FAK) to promote metastasis of epithelial ovarian cancer (EOC) cells. 62 In fibroblast and smooth muscle cells, CTHRC1 levels are associated with increased cell migration in vitro . 63 Other reports suggest that CTHRC1 may negatively regulate TGF-β-mediated signaling pathways. For example, Leclair et al. demonstrated that overexpression of CTHRC1 in smooth muscle cells reduced levels of phosphorylated Smad2/3, which is required for TGF-β-mediated gene expression and collagen production. 64 As Cthrc1 expression is enhanced in response to TGF-β in vitro , 63 mechanistic evidence suggests that TGF-β and CTHRC1 may act in a negative-feedback loop to limit TGF-β-induced ECM deposition. Due to conflicting reports on the role of CTHRC1 in a disease context, additional studies are required. Future queries delineating the precise relationship between CTHRC1 in TGF-β-mediated signaling and the role of CTHRC1 in a disease context must focus on cell- and tissue-specific mechanisms. Figure 3. Proposed mechanisms of CTHRC1- and BIGH3-mediated ECM modulation. (Left) TGF-β signaling enhances production of extracellular matrix proteins, as well as CTRHC1 , resulting in negative feedback loop limiting its own production. Secreted CTHRC1 can bind to collagens and integrins and has been implicated in cancer cell proliferation and migration by influencing Wnt and integrin β signaling pathways. (Right) TGF-β signaling enhances BIGH3 production which binds integrin receptors. Proposed pathways of BIGH3-mediated collagen production include activation of Snail and/or PI3K, transcription factors which influences collagen production as well as suppression of MMP14, which promotes collagen turnover. Legend: dashed lines represent prospective/predicted interactions. CTHRC1 has been shown to mark lung myofibroblasts in the context of models of lung fibrosis in murine systems and idiopathic pulmonary fibrosis (IPF) in humans. 20 , 60 , 65 – 67 Cthrc1 expression may also distinguish two disease-associated myofibroblast clusters across tissues. 20 One disease-associated myofibroblast cluster is marked by the simultaneous expression of Lrrc15 (leucine-rich repeat 15) and Cthrc1 expression, whereas the other is only marked by Cthrc1 and not Lrrc15 expression. 20 scRNA-seq-based characterization of collagen-producing cells in fibrotic mouse lungs demonstrated that the Cthrc1+ fibroblast cluster expresses the highest levels of ECM proteins, including Col1a1 and Col3a1 . 60 Tsukui et al. used transgenic mice to track and ablate Cthrc1 -expressing fibroblasts in lung fibrosis. Lineage tracing using Ctrhrc1-CreER mice crossed to Rosa26-tdTomato mice demonstrated that Cthrc1 -expressing lung fibroblasts expand in a mouse model of bleomycin-induced pulmonary fibrosis. Cthrc1 -Cre-ER-labeled cells showed elevated expression of ECM genes, including Col1a1 and Postn (periostin). Further, depletion of Cthrc1 -expressing lung fibroblasts using Cthrc1 -CreER mice crossed to Rosa26-tdTomato and Diphtheria toxin subunit A expressing mice attenuated hydroxyproline, a marker of collagen deposition following administration of bleomycin. 66 Taken together, these results suggest that Cthrc1 expressing cells drive ECM deposition and may promote fibrosis. Conversely, different studies have demonstrated that CTHRC1 may limit ECM deposition and fibrosis. Global Cthrc1 knock-out (KO) resulted in increased hydroxyproline levels and tissue remodeling in the lungs of mice following bleomycin administration. 65 In a mouse model of vascular fibrosis, Cthrc1 was transiently expressed by adventitial fibroblasts following injury and was associated with decreased collagen deposition in cross-sections of carotid arteries. 63 The discrepancies between these studies may highlight the cell-, tissue-, and disease-specific role of Cthrc1. As such, further studies are needed to determine the precise role of CTHRC1 in diverse fibrotic diseases. In addition, specific genetic tools, including fibroblast-specific Cthrc1 KO mice or fluorescently-labelled Cthrc1 -expressing cells are required to properly assess the pathogenicity of Cthrc1+ myofibroblasts in different tissues and disease models. BIGH3 is associated with increased collagen deposition Transforming growth factor beta inducible protein (TGFBI), is also known as keratoepithelian, 68 and is referred to here as beta-inducible growth hormone 3 (BIGH3) is produced by fibroblasts and macrophages. 69 BIGH3 was discovered in 1992 as a gene highly upregulated by A594 lung adenocarcinoma cells following TGF-β stimulation. 70 The structure of BIGH3 has not been solved; however, early characterization of this protein using cDNA sequence analysis suggested that it contains a secretory signal peptide, four fasciclin 1 (FAS1) domains that mediate binding to extracellular matrix proteins, such as collagens, and a RGD motif that enables the binding of this protein to integrin receptors. 70 – 72 Due to structural similarities, BIGH3 has been hypothesized to be a paralog of Periostin ( Postn ), 73 which drives collagen production in the presence of TGF-β. 74 BigH3 has been shown to be expressed by fibroblasts in response to stimulation with TGF-β 75 and by macrophages in ‘M2’ polarization conditions in vitro 60 , 61 , 76 or following ingestion of apoptotic cells. 69 Upon secretion by fibroblasts and macrophages, BIGH3 binds ECM components, such as collagens, 77 and subsequently binds the integrin a v b 5 78 and promotes adhesion and migration of mesenchymal and ectodermal-lineage cells, including fibroblasts, chrondrocytes, osteoblasts, keratinocytes, and endothelial cells. 79 – 81 Studies investigating the role of BIGH3 in disease indicated tissue-specific functions. In the central nervous system, Peng et al. demonstrated that BigH3 is elevated in the serum and cerebrospinal fluid (CSF) of glioblastoma patients and that TGFBI-expressing macrophages promoted the survival of glioma stem cells by avB5-Src-Stat3 signaling. 78 In the heart, Schwanekamp et al. demonstrated that BigH3 was enhanced in response to myocardial infarction. Despite this, cardiac-specific deletion of BigH3 did not alter cardiac disease or fibrosis post-myocardial infarction. 82 In the colon, TGF-β signalling plays a major role in promoting fibrotic lesions in inflammatory bowel diseases (IBD). 53 Aligned with this BigH3 , as well as ECM genes COL1A1 , COL1A2, and COL3A1 are upregulated in patients with fibrotic IBD, suggesting that combined BIGH3 and TGF-β signalling may accelerate colon fibrosis. 53 , 83 In the lungs, studies by Yang et al. and Xu et al. have independently demonstrated that BIGH3 is elevated in patients with interstitial lung disease. 84 , 85 Ahlfeld et al. demonstrated that BigH3 is elevated in response to lung injury and BigH3 KO mice at early ages had documented lung developmental abnormalities, lack of elastin-positive tips, reduced proliferation, and abnormally persistent aSMA myofibroblasts, which resolve by adulthood. 86 The authors also demonstrated that lungs in BigH3 deficient mice had reduced elastic recoil and gas exchange efficiency. 86 It remains to be seen if adult animals exhibit these defects or compensatory effects mask phenotypes seen in younger animals. In addition to impacting lung development, in vitro studies have demonstrated that BIGH3 can promote collagen deposition in lung fibroblasts. 87 Merl-Pham et al. demonstrated that TGF-β enhances the production of BigH3 in primary human lung fibroblasts. 88 Yang et al. found that siRNA-mediated knockdown (KD) of BigH3 in human lung fibroblast cultures resulted in decreased TGF-β-mediated collagen 1 (Col 1) and aSMA production, demonstrating that BIGH3 is necessary to produce these ECM proteins, 87 potentially through autocrine stimulation. Despite these studies, the molecular mechanism by which BIGH3 mediates Col1a1 deposition downstream of TGF-β is unclear. It has been posited based upon in vitro studies using lung fibroblast cell lines that BIGH3 mediates its effects via a multi-part mechanism. Briefly, TGF-β first elicits BIGH3 expression, then BIGH3 binds a multitude of integrin receptors, including a 1 b 1 , 89 a 3 b 1 , 90 , 91 a v b 3 79 or a v b 5 79 integrin. BigH3 then drives activation of PI3K-signaling 91 and increased Snail expression, encoded by Snail1 , via downregulation of a Snail negative regulator G-protein signaling modulator 2 (GPSM2). 79 , 87 Taken together, these studies revealed that BIGH3 is both necessary and sufficient to induce collagen production in lung fibroblasts. Therefore, mechanistic studies indicate that BIGH3 modulates TGF-β-mediated signal transduction pathways ( Figure 3B ). Alternative mechanisms for BIGH3-mediated regulation of collagen deposition in the lung have also been proposed. Zhang et al. demonstrated that BigH3 deficient mice had stunted growth in vivo, as well as enhanced proliferation and cyclin D1 expression ex vivo , suggesting that BIGH3 may limit cellular proliferation. 92 Nacu et al. demonstrated that primary lung fibroblasts stimulated with BIGH3 had increased Col 1 protein abundance in the absence of transcription, and subsequently demonstrated that BigH3 suppresses the transcription of MMP14, which degrades collagen. 69 These results suggest that BIGH3 reduces collagen turnover by decreasing ECM degradation. As a result of these conflicting reports, further study is required to characterize the full scope of ECM deposition changes in response to BIGH3. In addition to studies defining the tissue-specific nature of BIGH3 and the mechanisms of its effect on ECM deposition, further investigation is required into additional roles of BIGH3 in the context of fibroblasts and macrophage spatiality, including mechanical sensing, and/or monocyte/macrophage chemotaxis. As such, cell- and tissue- restricted BIGH3 KO models paired with high-resolution techniques, such as scRNA-seq are required to examine the role that BIGH3 plays in modulating ECM deposition, development, and disease. Conclusions The interface between fibroblasts, the immune system, and the ECM is wide and complex. As a result, an appreciation that fibroblasts and the immune system act in a finely tuned and integrated system for ECM deposition is required for understanding the biology of fibroblasts, as well as their roles in ECM deposition and fibrotic disease. Current research focuses on the relationship between fibroblasts and macrophages. As a result, additional studies are required to determine whether the relationships between fibroblasts and other immune cell subsets can shape ECM deposition or if macrophages are required as an intermediate. Despite this, targeting the fibroblast-ECM-immune axis may provide opportunities to prevent fibrotic disease. For example, defining the mechanism of action of immune-derived ECM modulators, including CTHRC1 and BIGH3, may provide an opportunity to modulate disease-associated myofibroblast development and/or prevent excessive fibrosis. Indeed, an attractive approach to ameliorate TGF-β related fibrosis may be to target potential co-factors or effect modulators within the TGF-β signaling pathway, such as CTHRC1 or BIGH3. It is possible that fibrotic deposition by fibroblasts is akin to accessing your online bank account using two-factor authentication: TGF-β representing the PIN and cofactors representing the code sent to your phone ( Figure 4 ). Here, TGF-β alone is a potent inducer of ECM-deposition in fibroblasts, whereas cofactors such as CTHRC1 or BIGH3 do not induce fibrosis alone. In combination, these cofactors increase TGF-β-mediated ECM deposition synergistically. To this end, we envision that intervention strategies specifically targeting TGF-β signalling cofactors (or the macrophage and myofibroblasts that produce them) may limit fibrotic disease and prevent off-target effects that are common among current therapies. Figure 4. Outlook regarding cofactor biology in ECM deposition and fibrotic disease. The role, mechanism, and source of cofactors, including BIGH3 and CTHRC1 in health and fibrotic disease are not well defined. Here, we speculate that fibroblasts are required for enhanced ECM deposition downstream of TGF-β, but cofactors alone are not sufficient, akin to accessing your online bank account using two-factor authentication: TGF-β representing the PIN and cofactors representing the code sent to your phone. 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Kim J-E, et al. : Identification of Motifs for Cell Adhesion within the Repeated Domains of Transforming Growth Factor-β-induced Gene,βig-h3. J. Biol. Chem. 2000; 275 : 30907–30915. PubMed Abstract | Publisher Full Text 91. Oh J-E, Kook J-K, Min B-M: βig-h3 Induces Keratinocyte Differentiation via Modulation of Involucrin and Transglutaminase Expression through the Integrin α3β1 and the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway. J. Biol. Chem. 2005; 280 : 21629–21637. PubMed Abstract | Publisher Full Text 92. Zhang Y, et al. : TGFBI Deficiency Predisposes Mice to Spontaneous Tumor Development. Cancer Res. 2009; 69 : 37–44. PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 19 Feb 2024 ADD YOUR COMMENT Comment Author details Author details 1 Immunology, University of Toronto, Toronto, Ontario, Canada Anthony Altieri Roles: Writing – Original Draft Preparation, Writing – Review & Editing Grace V. Visser Roles: Writing – Original Draft Preparation, Writing – Review & Editing Matthew B. Buechler Roles: Conceptualization, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This study was funded by Canadian Institutes of Health Research (471606) and Medicine by Design. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) version 2 Revised Published: 05 Dec 2024, 13:119 https://doi.org/10.12688/f1000research.143506.2 version 1 Published: 19 Feb 2024, 13:119 https://doi.org/10.12688/f1000research.143506.1 Copyright © 2024 Altieri A et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Altieri A, Visser GV and Buechler MB. Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.12688/f1000research.143506.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 05 Dec 2024 Revised Views 0 Cite How to cite this report: Kollias G. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.173782.r347955 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v2#referee-response-347955 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 11 Jan 2025 George Kollias , Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.173782.r347955 In the current review, Altieri et al . revisit the literature to highlight the ECM signals that mediate the fibroblast-macrophage interactions in the context of wound healing, fibrosis and cancer. They additionally summarize the current knowledge on the matrisome proteins CTHRC1 ... Continue reading READ ALL In the current review, Altieri et al . revisit the literature to highlight the ECM signals that mediate the fibroblast-macrophage interactions in the context of wound healing, fibrosis and cancer. They additionally summarize the current knowledge on the matrisome proteins CTHRC1 and TGFBI (BIGH3), and discuss their impact on ECM accumulation in fibrotic and malignant tissues. Overall, the manuscript is well-written and the authors comprehensively present the diverse nature of ECM signals (mechanical cues mediated by core matrisome proteins such as collagens, and biochemical signals mediated by matrisome-associated proteins, such as secreted factors (e.g. CSF1) and ECM regulators (MMP9)). Nonetheless, some major concerns need to be remarked: 1) The review’s title and abstract predispose the reader for a collection of studies that focus on the fibroblast-ECM-macrophage axis in fibrosis and cancer. Nevertheless, the manuscript's content does not align with its title, since the sender and/or receiver cell of the ECM signal is undefined in most of the references included. For example, in Figure 1 the authors schematically claim that fibroblast-secreted MMP9 promotes the accumulation of macrophages in the tissues. The respective studies by Shubayev et al ., Gong et al ., and Tan et al . indeed support the macrophage-recruiting role of MMP9, but they do not define the fibroblast as the cellular source of the enzyme. In the paper by Tan et al . in particular, the authors describe the tubular epithelial cells (TEC) as the major MMP9 producer. Consequently, Figure 1 should be modified accordingly to avoid misinterpretations. Additional ambiguity is detected regarding CTHRC1 and TGFBI. In the abstract, these molecules are defined as ‘fibroblast-derived ECM proteins’, whereas in the main text they are described as ‘immune-derived co-factor candidates’. Moreover, it does not become clear to the reader how the discussion on these proteins serves the purpose of the manuscript, given that no crosstalk between fibroblasts and macrophages through CTHRC1/TGFBI is reported. Overall, we recommend a cautious reconstruction of the text across the manuscript in a way that the references will reliably reflect the scope of the review. 2) Since fibroblast-macrophage interactions in fibrosis are in the spotlight of the review, the authors should consider dedicating a section to discuss the emerging topic of scar-associated macrophages (SAMacs) and how their communication with pro-fibrotic fibroblasts affects the disease course across tissues. This addition will be of particular relevance to the review’s main focus, as various ligands that have been described to mediate the crosstalk of the two fibrotic cell types constitute ECM-associated components (SPP1, IL-1β, PDGF), and are currently trending as potential antifibrotic therapeutic targets 1–6 . 3) Fibroblasts orchestrate ECM deposition in steady state and disease: In addition to the pathological consequences of aberrant fibroblast activation upon injury, it is worth mentioning the reviews by Koliaraki et al . (JEM, 2020 and Nature Immunology, 2020) 7,8 to also discuss the immunomodulatory effects of CAFs and ECM in the context of cancer. Is the topic of the review discussed comprehensively in the context of the current literature? Partly Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Partly References 1. Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, et al.: Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature . 2019; 575 (7783): 512-518 PubMed Abstract | Publisher Full Text 2. Hoeft K, Schaefer GJL, Kim H, Schumacher D, et al.: Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner. Cell Rep . 2023; 42 (2): 112131 PubMed Abstract | Publisher Full Text 3. Amrute JM, Luo X, Penna V, Yang S, et al.: Targeting immune-fibroblast cell communication in heart failure. Nature . 2024; 635 (8038): 423-433 PubMed Abstract | Publisher Full Text 4. Alexanian M, Padmanabhan A, Nishino T, Travers JG, et al.: Chromatin remodelling drives immune cell-fibroblast communication in heart failure. Nature . 2024; 635 (8038): 434-443 PubMed Abstract | Publisher Full Text 5. Kuppe C, Ramirez Flores RO, Li Z, Hayat S, et al.: Spatial multi-omic map of human myocardial infarction. Nature . 2022; 608 (7924): 766-777 PubMed Abstract | Publisher Full Text 6. Fabre T, Barron AMS, Christensen SM, Asano S, et al.: Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation. Sci Immunol . 2023; 8 (82): eadd8945 PubMed Abstract | Publisher Full Text 7. Koliaraki V, Henriques A, Prados A, Kollias G: Unfolding innate mechanisms in the cancer microenvironment: The emerging role of the mesenchyme. J Exp Med . 2020; 217 (4). PubMed Abstract | Publisher Full Text 8. Koliaraki V, Prados A, Armaka M, Kollias G: The mesenchymal context in inflammation, immunity and cancer. Nat Immunol . 2020; 21 (9): 974-982 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Inflammatory diseases, Intestinal fibrosis, Colon cancer I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Kollias G. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.173782.r347955 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v2#referee-response-347955 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Makris S. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.173782.r347953 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v2#referee-response-347953 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 07 Jan 2025 Spyridon Makris , University College London, London, UK Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.173782.r347953 This review provides valuable insight on the complex interactions between fibroblasts and macrophages in health and disease. The authors elegantly link multiple scRNA-seq, and other transcriptional studies, across multiple tissues to describe the importance of ECM deposition by fibroblast in ... Continue reading READ ALL This review provides valuable insight on the complex interactions between fibroblasts and macrophages in health and disease. The authors elegantly link multiple scRNA-seq, and other transcriptional studies, across multiple tissues to describe the importance of ECM deposition by fibroblast in health and disease. This review is important as it examines the fibroblast:macrophage crosstalk and how it can affect disease outcome. The authors use a large variety of studies to show to show how fibroblasts can alter organ structural properties and regulate the immune responses by secreting ECM and ECM-bound molecules. There is particular focus on ECM-derived proteins, CTHRC1 and TGFBI (BIGH3), as modulators of the ECM proteins. As the authors rightly state, more studies on the crosstalk between fibroblasts and immune cells and how that would affect ECM deposition. Finally, they describe methods by which the TGF-beta signalling cofactors could provide potential therapeutic targets. Minor Points : Figure 2 not easy to comprehend and in its current form. It would benefit if authors rearranged the figure slightly and provided numbers. The reader should then be able to follow how fibroblast transition toward heterogeneity occurs and how that would link to changes in ECM remodelling, Cell recruitment and ECM regulation of co-factors. At end of ECM form & function section, letters are missing after IFN-, TNF- and IL-1. Figure sizes are not identical and it is difficult to read the small text in Figure 3. I suggest the authors adjust both the font and figure sizes to make it easier for the reader. Figure 3 Merge the initial heading “Matrix remodeling, cell migration, Collagen production” Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Yes Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Immunology, Stromal Immunology, Virology, Respiratory infections, Innate immunity I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Makris S. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.173782.r347953 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v2#referee-response-347953 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Pucino V. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.173782.r346224 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v2#referee-response-346224 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 06 Dec 2024 Valentina Pucino , Kennedy Institute of rheumatology, Oxford University, Oxford, UK; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Tuscany, Italy Approved VIEWS 0 https://doi.org/10.5256/f1000research.173782.r346224 The authors answered to all my comments and I have no further comments to ... Continue reading READ ALL The authors answered to all my comments and I have no further comments to make. I am happy for the paper to be indexed in the current version. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Immunology, Immunometabolism, fibroblast biology, T cell biology, autoimmunity. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Pucino V. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.173782.r346224 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v2#referee-response-346224 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 19 Feb 2024 Views 0 Cite How to cite this report: Pucino V. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.157178.r262987 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v1#referee-response-262987 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 17 May 2024 Valentina Pucino , Kennedy Institute of rheumatology, Oxford University, Oxford, UK; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Tuscany, Italy Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.157178.r262987 I find this review timely and well written. It summarizes the latest findings on fibroblast biology and fibroblast-derived molecules offering an insight on potential therapeutic options to target fibroblast-mediated diseases such as fibrosis where therapeutic treatments are lacking. This is ... Continue reading READ ALL I find this review timely and well written. It summarizes the latest findings on fibroblast biology and fibroblast-derived molecules offering an insight on potential therapeutic options to target fibroblast-mediated diseases such as fibrosis where therapeutic treatments are lacking. This is a hot topic at the moment. See detailed report below. This review from Altieri et al. recapitulates the most recent findings in the field of fibroblasts. In addition, the authors discuss how fibroblasts coordinate immune responses, especially macrophages’ functions, by modulating ECM, and outline the molecular mediators such as CTHRC1 and TGFB and pathways regulating these processes. This is a very well written and timely review. Minor points: Add and discuss the following references: Fibroblasts orchestrate ECM deposition in steady state and disease : I would add few more words on fibroblasts heterogeneity here. Some key references below: Gauthier V,et.al., 2023 [Ref 1], Korsunsky I, et.al.,2022 [Ref 2], Muhl L, et.al., 2020 [3] ECM form & function : it’s worth to mention and discuss the paper by Horsnell et al 2023 in addition to reference number 4. Fibroblast derived cytokines and chemokines decorate the ECM to influence fibroblast-macrophage interactions : please add and discuss the following references which focus on fibroblast/macrophage interactions. Ng MTH, et.al.,2024 [Ref 5],Zhou X, et.al.,2022 [Ref 6], Meizlish ML, et.al., 2024 [Ref 7] Recent evidence has demonstrated that metabolic intermediates can also fuel stromal cell responses and ECM deposition and can regulate cellular crosstalk. Kay EJ, et.al., 2022 [Ref 8], Schwörer S,et.al.,2021 [Ref 9], Pucino V, et.al., 2023 [Ref 10] Major point: The proposed model at the end of the article is not very clear and can be improved. Is the topic of the review discussed comprehensively in the context of the current literature? Partly Are all factual statements correct and adequately supported by citations? Yes Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Partly References 1. Gauthier V, Kyriazi M, Nefla M, Pucino V, et al.: Fibroblast heterogeneity: Keystone of tissue homeostasis and pathology in inflammation and ageing. Front Immunol . 2023; 14 : 1137659 PubMed Abstract | Publisher Full Text 2. Korsunsky I, Wei K, Pohin M, Kim EY, et al.: Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med . 2022; 3 (7): 481-518.e14 PubMed Abstract | Publisher Full Text 3. Muhl L, Genové G, Leptidis S, Liu J, et al.: Publisher Correction: Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination. Nat Commun . 2020; 11 (1): 4493 PubMed Abstract | Publisher Full Text 4. Horsnell HL, Tetley RJ, De Belly H, Makris S, et al.: Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics. Nat Immunol . 2022; 23 (8): 1169-1182 PubMed Abstract | Publisher Full Text 5. Ng MTH, Borst R, Gacaferi H, Davidson S, et al.: A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution. Nat Commun . 2024; 15 (1): 1394 PubMed Abstract | Publisher Full Text 6. Zhou X, Franklin RA, Adler M, Carter TS, et al.: Microenvironmental sensing by fibroblasts controls macrophage population size. Proc Natl Acad Sci U S A . 2022; 119 (32): e2205360119 PubMed Abstract | Publisher Full Text 7. Meizlish ML, Kimura Y, Pope SD, Matta R, et al.: Mechanosensing regulates tissue repair program in macrophages. Sci Adv . 2024; 10 (11): eadk6906 PubMed Abstract | Publisher Full Text 8. Kay EJ, Paterson K, Riera-Domingo C, Sumpton D, et al.: Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nat Metab . 2022; 4 (6): 693-710 PubMed Abstract | Publisher Full Text 9. Schwörer S, Pavlova NN, Cimino FV, King B, et al.: Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment. Nat Metab . 2021; 3 (11): 1484-1499 PubMed Abstract | Publisher Full Text 10. Pucino V, Nefla M, Gauthier V, Alsaleh G, et al.: Differential effect of lactate on synovial fibroblast and macrophage effector functions. Front Immunol . 2023; 14 : 1183825 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Immunology, Immunometabolism, fibroblast biology, T cell biology, autoimmunity. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Pucino V. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.157178.r262987 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v1#referee-response-262987 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Wietecha MS. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.157178.r262986 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v1#referee-response-262986 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 07 May 2024 Mateusz S. Wietecha , University of Illinois Chicago, Chicago, Illinois, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.157178.r262986 In this review article, the authors describe the functions of fibroblasts in the context of ECM remodeling and their interaction with macrophages, and make the claim that CTHRC1 and TGFBI are important modulators of this axis. Overall, the manuscript is ... Continue reading READ ALL In this review article, the authors describe the functions of fibroblasts in the context of ECM remodeling and their interaction with macrophages, and make the claim that CTHRC1 and TGFBI are important modulators of this axis. Overall, the manuscript is well-written. However, the manuscript is uneven in how it presents information. As I outline below, some sections of the manuscript are overly superficial in their discussion of important concepts and rely on citing review articles rather than primary research papers. Meanwhile, some of the other sections of the manuscript simply list findings from primary research studies without providing a proper context for the reader to understand the findings. The two main themes of fibroblast-macrophage interactions and CTHRC1/TGFBI functions read like two separate narratives, and the connection between the two needs to made much more clear by the authors. The following are a few suggestions to improve the manuscript: 1. The title should be changed to reflect the rather narrow focus on either fibroblast-macrophage interactions and/or the roles of CTHRC1 and TGFBI. 2. In general, the manuscript cites too many other reviews, especially when referring to specific facts/findings that should really be citing the original research papers that originated these findings. 3. Intro, paragraphs 2-4, and section on "fibroblast heterogeneity dictates ECM deposition": the discussion about fibroblasts' heterogeneity and their myriad functions during wound repair and fibrosis is overly simplistic, as is the depiction in Figure 2. In addition to the discussed ref. 34, there are several other recent primary research papers that should be cited and discussed here that directly address fibroblast heterogeneity and its effects on ECM composition during wound repair; see for example references Guerrero-Juarez CF et.al., 2019 (Ref 1), Gay Det.al., 2020 (Ref 2), Foster DSet.al.,2021 (Ref 3), Wietecha MS et.al., 2023 (Ref 4), Phan QM et.al., 2021 (Ref 5), Hu KH et.al., 2023 (Ref 6) below. Many of these papers also mention fibroblast-macrophage interactions and list CTHRC1 and TGFBI as genes of interest, but this requires a deeper dive that may better set the stage for the more focused discussion about TGF-beta signaling, CTHRC1 and BIGH3. 4. The sections on CTHRC1 and BIGH3 are a list of facts about their function in fibroblasts in various model systems and have very little to do with macrophages or fibroblast-macrophage interactions dictating ECM composition in disease states. Besides a couple sentences stating that both CTHRC1 and BIGH3 may also be produced by macrophages, how does this fit within the larger narrative the authors have established thus far? Are macrophages even the primary producers of these cofactors in disease states, or are fibroblasts? Indeed, the "proposed model for cofactor-mediated ECM deposition in fibroblasts" (Fig 4) does not show macrophages as producers of CTHRC1/BIGH3. 5. The statement "This gene is also a paralog of periostin (POSTN)" lacks context and explanation. Is the topic of the review discussed comprehensively in the context of the current literature? Partly Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Partly References 1. Guerrero-Juarez CF, Dedhia PH, Jin S, Ruiz-Vega R, et al.: Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds. Nat Commun . 2019; 10 (1): 650 PubMed Abstract | Publisher Full Text 2. Gay D, Ghinatti G, Guerrero-Juarez CF, Ferrer RA, et al.: Phagocytosis of Wnt inhibitor SFRP4 by late wound macrophages drives chronic Wnt activity for fibrotic skin healing. Sci Adv . 2020; 6 (12): eaay3704 PubMed Abstract | Publisher Full Text 3. Foster DS, Januszyk M, Yost KE, Chinta MS, et al.: Integrated spatial multiomics reveals fibroblast fate during tissue repair. Proc Natl Acad Sci U S A . 2021; 118 (41). PubMed Abstract | Publisher Full Text 4. Wietecha MS, Lauenstein D, Cangkrama M, Seiler S, et al.: Phase-specific signatures of wound fibroblasts and matrix patterns define cancer-associated fibroblast subtypes. Matrix Biol . 2023; 119 : 19-56 PubMed Abstract | Publisher Full Text 5. Phan QM, Sinha S, Biernaskie J, Driskell RR: Single-cell transcriptomic analysis of small and large wounds reveals the distinct spatial organization of regenerative fibroblasts. Exp Dermatol . 2021; 30 (1): 92-101 PubMed Abstract | Publisher Full Text 6. Hu KH, Kuhn NF, Courau T, Tsui J, et al.: Transcriptional space-time mapping identifies concerted immune and stromal cell patterns and gene programs in wound healing and cancer. Cell Stem Cell . 2023; 30 (6): 885-903.e10 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: wound healing, fibroblasts, bioinformatics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Wietecha MS. Reviewer Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.157178.r262986 ) The direct URL for this report is: https://f1000research.com/articles/13-119/v1#referee-response-262986 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 19 Feb 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 4 Version 2 (revision) 05 Dec 24 read read read Version 1 19 Feb 24 read read Mateusz S. Wietecha , University of Illinois Chicago, Chicago, USA Valentina Pucino , Oxford University, Oxford, UK; University of Pisa, Pisa, Italy Spyridon Makris , University College London, London, UK George Kollias , Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Kollias G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 11 Jan 2025 | for Version 2 George Kollias , Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece 0 Views copyright © 2025 Kollias G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In the current review, Altieri et al . revisit the literature to highlight the ECM signals that mediate the fibroblast-macrophage interactions in the context of wound healing, fibrosis and cancer. They additionally summarize the current knowledge on the matrisome proteins CTHRC1 and TGFBI (BIGH3), and discuss their impact on ECM accumulation in fibrotic and malignant tissues. Overall, the manuscript is well-written and the authors comprehensively present the diverse nature of ECM signals (mechanical cues mediated by core matrisome proteins such as collagens, and biochemical signals mediated by matrisome-associated proteins, such as secreted factors (e.g. CSF1) and ECM regulators (MMP9)). Nonetheless, some major concerns need to be remarked: 1) The review’s title and abstract predispose the reader for a collection of studies that focus on the fibroblast-ECM-macrophage axis in fibrosis and cancer. Nevertheless, the manuscript's content does not align with its title, since the sender and/or receiver cell of the ECM signal is undefined in most of the references included. For example, in Figure 1 the authors schematically claim that fibroblast-secreted MMP9 promotes the accumulation of macrophages in the tissues. The respective studies by Shubayev et al ., Gong et al ., and Tan et al . indeed support the macrophage-recruiting role of MMP9, but they do not define the fibroblast as the cellular source of the enzyme. In the paper by Tan et al . in particular, the authors describe the tubular epithelial cells (TEC) as the major MMP9 producer. Consequently, Figure 1 should be modified accordingly to avoid misinterpretations. Additional ambiguity is detected regarding CTHRC1 and TGFBI. In the abstract, these molecules are defined as ‘fibroblast-derived ECM proteins’, whereas in the main text they are described as ‘immune-derived co-factor candidates’. Moreover, it does not become clear to the reader how the discussion on these proteins serves the purpose of the manuscript, given that no crosstalk between fibroblasts and macrophages through CTHRC1/TGFBI is reported. Overall, we recommend a cautious reconstruction of the text across the manuscript in a way that the references will reliably reflect the scope of the review. 2) Since fibroblast-macrophage interactions in fibrosis are in the spotlight of the review, the authors should consider dedicating a section to discuss the emerging topic of scar-associated macrophages (SAMacs) and how their communication with pro-fibrotic fibroblasts affects the disease course across tissues. This addition will be of particular relevance to the review’s main focus, as various ligands that have been described to mediate the crosstalk of the two fibrotic cell types constitute ECM-associated components (SPP1, IL-1β, PDGF), and are currently trending as potential antifibrotic therapeutic targets 1–6 . 3) Fibroblasts orchestrate ECM deposition in steady state and disease: In addition to the pathological consequences of aberrant fibroblast activation upon injury, it is worth mentioning the reviews by Koliaraki et al . (JEM, 2020 and Nature Immunology, 2020) 7,8 to also discuss the immunomodulatory effects of CAFs and ECM in the context of cancer. Is the topic of the review discussed comprehensively in the context of the current literature? Partly Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Partly References 1. Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, et al.: Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature . 2019; 575 (7783): 512-518 PubMed Abstract | Publisher Full Text 2. Hoeft K, Schaefer GJL, Kim H, Schumacher D, et al.: Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner. Cell Rep . 2023; 42 (2): 112131 PubMed Abstract | Publisher Full Text 3. Amrute JM, Luo X, Penna V, Yang S, et al.: Targeting immune-fibroblast cell communication in heart failure. Nature . 2024; 635 (8038): 423-433 PubMed Abstract | Publisher Full Text 4. Alexanian M, Padmanabhan A, Nishino T, Travers JG, et al.: Chromatin remodelling drives immune cell-fibroblast communication in heart failure. Nature . 2024; 635 (8038): 434-443 PubMed Abstract | Publisher Full Text 5. Kuppe C, Ramirez Flores RO, Li Z, Hayat S, et al.: Spatial multi-omic map of human myocardial infarction. Nature . 2022; 608 (7924): 766-777 PubMed Abstract | Publisher Full Text 6. Fabre T, Barron AMS, Christensen SM, Asano S, et al.: Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation. Sci Immunol . 2023; 8 (82): eadd8945 PubMed Abstract | Publisher Full Text 7. Koliaraki V, Henriques A, Prados A, Kollias G: Unfolding innate mechanisms in the cancer microenvironment: The emerging role of the mesenchyme. J Exp Med . 2020; 217 (4). PubMed Abstract | Publisher Full Text 8. Koliaraki V, Prados A, Armaka M, Kollias G: The mesenchymal context in inflammation, immunity and cancer. Nat Immunol . 2020; 21 (9): 974-982 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Inflammatory diseases, Intestinal fibrosis, Colon cancer I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Kollias G. Peer Review Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.173782.r347955) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-119/v2#referee-response-347955 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Makris S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 07 Jan 2025 | for Version 2 Spyridon Makris , University College London, London, UK 0 Views copyright © 2025 Makris S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This review provides valuable insight on the complex interactions between fibroblasts and macrophages in health and disease. The authors elegantly link multiple scRNA-seq, and other transcriptional studies, across multiple tissues to describe the importance of ECM deposition by fibroblast in health and disease. This review is important as it examines the fibroblast:macrophage crosstalk and how it can affect disease outcome. The authors use a large variety of studies to show to show how fibroblasts can alter organ structural properties and regulate the immune responses by secreting ECM and ECM-bound molecules. There is particular focus on ECM-derived proteins, CTHRC1 and TGFBI (BIGH3), as modulators of the ECM proteins. As the authors rightly state, more studies on the crosstalk between fibroblasts and immune cells and how that would affect ECM deposition. Finally, they describe methods by which the TGF-beta signalling cofactors could provide potential therapeutic targets. Minor Points : Figure 2 not easy to comprehend and in its current form. It would benefit if authors rearranged the figure slightly and provided numbers. The reader should then be able to follow how fibroblast transition toward heterogeneity occurs and how that would link to changes in ECM remodelling, Cell recruitment and ECM regulation of co-factors. At end of ECM form & function section, letters are missing after IFN-, TNF- and IL-1. Figure sizes are not identical and it is difficult to read the small text in Figure 3. I suggest the authors adjust both the font and figure sizes to make it easier for the reader. Figure 3 Merge the initial heading “Matrix remodeling, cell migration, Collagen production” Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Yes Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Immunology, Stromal Immunology, Virology, Respiratory infections, Innate immunity I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Makris S. Peer Review Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.173782.r347953) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-119/v2#referee-response-347953 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Pucino V. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 06 Dec 2024 | for Version 2 Valentina Pucino , Kennedy Institute of rheumatology, Oxford University, Oxford, UK; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Tuscany, Italy 0 Views copyright © 2024 Pucino V. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors answered to all my comments and I have no further comments to make. I am happy for the paper to be indexed in the current version. Competing Interests No competing interests were disclosed. Reviewer Expertise Immunology, Immunometabolism, fibroblast biology, T cell biology, autoimmunity. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Pucino V. Peer Review Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.173782.r346224) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-119/v2#referee-response-346224 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Pucino V. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 17 May 2024 | for Version 1 Valentina Pucino , Kennedy Institute of rheumatology, Oxford University, Oxford, UK; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Tuscany, Italy 0 Views copyright © 2024 Pucino V. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I find this review timely and well written. It summarizes the latest findings on fibroblast biology and fibroblast-derived molecules offering an insight on potential therapeutic options to target fibroblast-mediated diseases such as fibrosis where therapeutic treatments are lacking. This is a hot topic at the moment. See detailed report below. This review from Altieri et al. recapitulates the most recent findings in the field of fibroblasts. In addition, the authors discuss how fibroblasts coordinate immune responses, especially macrophages’ functions, by modulating ECM, and outline the molecular mediators such as CTHRC1 and TGFB and pathways regulating these processes. This is a very well written and timely review. Minor points: Add and discuss the following references: Fibroblasts orchestrate ECM deposition in steady state and disease : I would add few more words on fibroblasts heterogeneity here. Some key references below: Gauthier V,et.al., 2023 [Ref 1], Korsunsky I, et.al.,2022 [Ref 2], Muhl L, et.al., 2020 [3] ECM form & function : it’s worth to mention and discuss the paper by Horsnell et al 2023 in addition to reference number 4. Fibroblast derived cytokines and chemokines decorate the ECM to influence fibroblast-macrophage interactions : please add and discuss the following references which focus on fibroblast/macrophage interactions. Ng MTH, et.al.,2024 [Ref 5],Zhou X, et.al.,2022 [Ref 6], Meizlish ML, et.al., 2024 [Ref 7] Recent evidence has demonstrated that metabolic intermediates can also fuel stromal cell responses and ECM deposition and can regulate cellular crosstalk. Kay EJ, et.al., 2022 [Ref 8], Schwörer S,et.al.,2021 [Ref 9], Pucino V, et.al., 2023 [Ref 10] Major point: The proposed model at the end of the article is not very clear and can be improved. Is the topic of the review discussed comprehensively in the context of the current literature? Partly Are all factual statements correct and adequately supported by citations? Yes Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Partly References 1. Gauthier V, Kyriazi M, Nefla M, Pucino V, et al.: Fibroblast heterogeneity: Keystone of tissue homeostasis and pathology in inflammation and ageing. Front Immunol . 2023; 14 : 1137659 PubMed Abstract | Publisher Full Text 2. Korsunsky I, Wei K, Pohin M, Kim EY, et al.: Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med . 2022; 3 (7): 481-518.e14 PubMed Abstract | Publisher Full Text 3. Muhl L, Genové G, Leptidis S, Liu J, et al.: Publisher Correction: Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination. Nat Commun . 2020; 11 (1): 4493 PubMed Abstract | Publisher Full Text 4. Horsnell HL, Tetley RJ, De Belly H, Makris S, et al.: Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics. Nat Immunol . 2022; 23 (8): 1169-1182 PubMed Abstract | Publisher Full Text 5. Ng MTH, Borst R, Gacaferi H, Davidson S, et al.: A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution. Nat Commun . 2024; 15 (1): 1394 PubMed Abstract | Publisher Full Text 6. Zhou X, Franklin RA, Adler M, Carter TS, et al.: Microenvironmental sensing by fibroblasts controls macrophage population size. Proc Natl Acad Sci U S A . 2022; 119 (32): e2205360119 PubMed Abstract | Publisher Full Text 7. Meizlish ML, Kimura Y, Pope SD, Matta R, et al.: Mechanosensing regulates tissue repair program in macrophages. Sci Adv . 2024; 10 (11): eadk6906 PubMed Abstract | Publisher Full Text 8. Kay EJ, Paterson K, Riera-Domingo C, Sumpton D, et al.: Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nat Metab . 2022; 4 (6): 693-710 PubMed Abstract | Publisher Full Text 9. Schwörer S, Pavlova NN, Cimino FV, King B, et al.: Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment. Nat Metab . 2021; 3 (11): 1484-1499 PubMed Abstract | Publisher Full Text 10. Pucino V, Nefla M, Gauthier V, Alsaleh G, et al.: Differential effect of lactate on synovial fibroblast and macrophage effector functions. Front Immunol . 2023; 14 : 1183825 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Immunology, Immunometabolism, fibroblast biology, T cell biology, autoimmunity. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Pucino V. Peer Review Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.157178.r262987) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-119/v1#referee-response-262987 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Wietecha M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 07 May 2024 | for Version 1 Mateusz S. Wietecha , University of Illinois Chicago, Chicago, Illinois, USA 0 Views copyright © 2024 Wietecha M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In this review article, the authors describe the functions of fibroblasts in the context of ECM remodeling and their interaction with macrophages, and make the claim that CTHRC1 and TGFBI are important modulators of this axis. Overall, the manuscript is well-written. However, the manuscript is uneven in how it presents information. As I outline below, some sections of the manuscript are overly superficial in their discussion of important concepts and rely on citing review articles rather than primary research papers. Meanwhile, some of the other sections of the manuscript simply list findings from primary research studies without providing a proper context for the reader to understand the findings. The two main themes of fibroblast-macrophage interactions and CTHRC1/TGFBI functions read like two separate narratives, and the connection between the two needs to made much more clear by the authors. The following are a few suggestions to improve the manuscript: 1. The title should be changed to reflect the rather narrow focus on either fibroblast-macrophage interactions and/or the roles of CTHRC1 and TGFBI. 2. In general, the manuscript cites too many other reviews, especially when referring to specific facts/findings that should really be citing the original research papers that originated these findings. 3. Intro, paragraphs 2-4, and section on "fibroblast heterogeneity dictates ECM deposition": the discussion about fibroblasts' heterogeneity and their myriad functions during wound repair and fibrosis is overly simplistic, as is the depiction in Figure 2. In addition to the discussed ref. 34, there are several other recent primary research papers that should be cited and discussed here that directly address fibroblast heterogeneity and its effects on ECM composition during wound repair; see for example references Guerrero-Juarez CF et.al., 2019 (Ref 1), Gay Det.al., 2020 (Ref 2), Foster DSet.al.,2021 (Ref 3), Wietecha MS et.al., 2023 (Ref 4), Phan QM et.al., 2021 (Ref 5), Hu KH et.al., 2023 (Ref 6) below. Many of these papers also mention fibroblast-macrophage interactions and list CTHRC1 and TGFBI as genes of interest, but this requires a deeper dive that may better set the stage for the more focused discussion about TGF-beta signaling, CTHRC1 and BIGH3. 4. The sections on CTHRC1 and BIGH3 are a list of facts about their function in fibroblasts in various model systems and have very little to do with macrophages or fibroblast-macrophage interactions dictating ECM composition in disease states. Besides a couple sentences stating that both CTHRC1 and BIGH3 may also be produced by macrophages, how does this fit within the larger narrative the authors have established thus far? Are macrophages even the primary producers of these cofactors in disease states, or are fibroblasts? Indeed, the "proposed model for cofactor-mediated ECM deposition in fibroblasts" (Fig 4) does not show macrophages as producers of CTHRC1/BIGH3. 5. The statement "This gene is also a paralog of periostin (POSTN)" lacks context and explanation. Is the topic of the review discussed comprehensively in the context of the current literature? Partly Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Partly References 1. Guerrero-Juarez CF, Dedhia PH, Jin S, Ruiz-Vega R, et al.: Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds. Nat Commun . 2019; 10 (1): 650 PubMed Abstract | Publisher Full Text 2. Gay D, Ghinatti G, Guerrero-Juarez CF, Ferrer RA, et al.: Phagocytosis of Wnt inhibitor SFRP4 by late wound macrophages drives chronic Wnt activity for fibrotic skin healing. Sci Adv . 2020; 6 (12): eaay3704 PubMed Abstract | Publisher Full Text 3. Foster DS, Januszyk M, Yost KE, Chinta MS, et al.: Integrated spatial multiomics reveals fibroblast fate during tissue repair. Proc Natl Acad Sci U S A . 2021; 118 (41). PubMed Abstract | Publisher Full Text 4. Wietecha MS, Lauenstein D, Cangkrama M, Seiler S, et al.: Phase-specific signatures of wound fibroblasts and matrix patterns define cancer-associated fibroblast subtypes. Matrix Biol . 2023; 119 : 19-56 PubMed Abstract | Publisher Full Text 5. Phan QM, Sinha S, Biernaskie J, Driskell RR: Single-cell transcriptomic analysis of small and large wounds reveals the distinct spatial organization of regenerative fibroblasts. Exp Dermatol . 2021; 30 (1): 92-101 PubMed Abstract | Publisher Full Text 6. Hu KH, Kuhn NF, Courau T, Tsui J, et al.: Transcriptional space-time mapping identifies concerted immune and stromal cell patterns and gene programs in wound healing and cancer. Cell Stem Cell . 2023; 30 (6): 885-903.e10 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise wound healing, fibroblasts, bioinformatics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Wietecha MS. Peer Review Report For: Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease. [version 2; peer review: 1 approved, 3 approved with reservations] . F1000Research 2024, 13 :119 ( https://doi.org/10.5256/f1000research.157178.r262986) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-119/v1#referee-response-262986 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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