Decidual stromal cells: fibroblasts specialized in immunoregulation during pregnancy

UNCORRECTED PROOF 1 2 Review 3Q5 Decidual stromal cells: fibroblasts specialized in 4 immunoregulation during pregnancy 5Q6Q7 Tatiana Llorca 1, María J. Ruiz-Magaña 1,2,*, Ana C. Abadía 1,3, Carmen Ruiz-Ruiz 1,3, and 6 Enrique G. Olivares 1,3,* 7 Decidual stromal cells (DSCs) are involved in immunoregulatory mechanisms 8 that prevent fetal rejection by the mammalian maternal immune system. Recent 9 studies using single-cell RNA sequencing demonstrated the existence of differ- 10 ent types of human and mouse DSCs, highlighting corresponding differentiation 11 (decidualization) pathways, and suggesting their involvement in the immune 12 response during normal and pathological pregnancy. DSCs may be considered 13 tissue-specialized fibroblasts because both DSCs and fibroblasts share pheno- 14 typic and functional similarities in immunologically challenged tissues, especially 15 in terms of their immune functions. Indeed, fibroblasts can initiate, support, or 16 suppress immune responses and these functions are also performed by DSCs. 17 Moreover, fibroblasts and DSCs can induce ectopic foci as tertiary lymphoid 18 structures (TLSs), but also contribute to endometriosis. Thus, understanding 19 DSC immunoregulatory functions is of timely relevance.20Q8 21 DSCs and pregnancy homeostasis 22 It is well-established that DSCs are the most abundant cell type in first-trimester human decidua 23 (≈50%) (Figure 1A), the maternal part of theplacenta (see Glossary), which is in close contact with 24 the fetal trophoblast. The decidua is derived from the non-pregnant endometrium, which differ- 25 entiates into the decidua through the effects of progesterone (P4) and other pregnancy hormones 26 when pregnancy occurs. This process, called decidualization, involves all endometrial/decidual cell 27 types, and prepares the endometrium forimplantationof the blastocyst. Pregnancy can be con- 28 sidered a semi-allogeneic graft in which the maternal immune system establishes various local and 29 systemic mechanisms to prevent fetal rejection [1]( Box 1). In mice and humans, DSCs are involved 30 in the control of trophoblastic invasion into the decidua and participate in local immunoregulatory 31 activities by interacting with different decidual immune cells (Box 2)[ 2–5]. Single-cell RNA sequenc- 32 ing (ScRNAseq) technology has made it possible to distinguish different types of DSCs andendo- 33 metrial stromal cells (EnSCs)– the endometrial counterpart of DSCs– and to infer their possible 34 functionality and interactions with decidual or endometrial immune cells [6–8]. ScRNAseq has also 35 provided insights into the involvement of DSCs in labor onset [ 9–12] and in various obstetric and 36 gynecological pathologies [ 13–15]. DSCs are derived from perivascular precursors (preDSCs) 37 with fibroblastic morphology which, under the effect of P4 and other pregnancy hormones, differ- 38 entiate (decidualize) into rounded or polygonal cells that leave the vessels and occupy extravascular 39 spaces [decidualized DSCs (dDSCs)] (Figure 1)[ 16]. dDSCs secrete prolactin (PRL) and insulin-like 40 growth factor-binding protein1 (IGFBP-1), both of which are considered to be markers of 41 decidualization [17]. The establishment of human DSC lines from first-trimester human decidua 42 has made it possible to study the antigenic phenotype and some of the functions of these cells 43 [18–20]( Table 1 ). In the absence of decidualizing factors (P4 + cAMP) in the culture medium, 44 DSC lines consist of preDSCs, cells with fibroblastic morphology that do not secrete PRL. How- 45 ever, when P4 and cAMP are added to the culture medium in vitro , preDSCs decidualize into Highlights Mammalian decidual stromal cells (DSC) control trophoblast invasion into the decidua during pregnancy and play a role in maternal–fetal immune tolerance. Recent single-cell RNA sequencing (ScRNAseq) studies demonstrated the existence of different DSC populations with different functions: angiogenesis, immunoregulation, and involvement in the onset of labor. ScRNAseq analysis also implicated DSCs and endometrial stromal cells (EnSC) in immune-mediated obstetric and gynecological pathologies, such as recurrent pregnancy loss (RPL), preterm birth, pre-eclampsia, and endometriosis. Secondary lymphoid organ (SLO) fibroblasts and non-SLO fibroblasts set up, support, and suppress immune responses. Functional and transcriptomic studies and antigenic phenotyping provide evi- dence of a close relationship between DSCs and fibroblasts of immunologically active tissues. Significance Human decidual stromal cells (DSCs) can be considered tissue-specialized fibroblasts, because they share pheno- typic and functional similarities withfibro- blasts of immunologically challenged tissues, particularly in terms of immune functions. The identification of common functions and molecules responsible for these activities may help to further un- derstand the physiology of these stromal cells interacting with immune cells during pregnancy and non-pregnancy. This may help uncover potential targets for treating diseases associated with DSCs. Trends in Immunology, Month 2025, Vol. xx, No. xx https://doi.org/10.1016/j.it.2024.12.007 1 © 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies. Trends in Immunology TREIMM 2208 No. of Pages 15 UNCORRECTED PR OOF TrendsTrends inin ImmunologyImmunology Q2 Figure 1. Decidual stromal cells (DSCs) infirst-trimester human decidua. (A) The representative micrograph shows a semithin cryostatic section of early human decidua stained with toluidine blue, indicating the DSC precursors (preDSCs, black arrows) and decidualized DSCs (dDSCs, red arrows). Scale bar: 50 μm (B) The representative micrographs show perivascular α-SM actin-positive cells (yellow) coexpressing CD 140b, CD146, and SUSD2. Endothelial cells are stained with anti-CD34-antibody (blue). Scale bars: 100 μm. (C) The cartoon depicts decidualization from preDSCs to dDSCs. The expression of molecules is characteristic of each stage of differentiation. Top shows scanning electron micrographs of a preDSC and a dDSC from a cultured DSC line. Abbreviations: α-SM actin, alpha-smooth muscle actin; BAFF-R, B cell activating factor receptor; IGF1, insulin-like growth factor 1; IGFBP-1, insulin-like growth factor-binding protein1; MFGE8, milk fat globule-epidermal growth factor 8; P4, progesterone; PRL, prolactin; SUSD2, sushi domain-containing 2. Figure 1 B created with BioRender.com . Figure 1 Af r o m[ 18], with permission. Figure 1 Bf r o m[ 16], with permission. Figure 1C, scanning electron micrographs from [ 119], Q1 with permission. 1Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain 2Departamento de Biología Celular, Universidad de Granada, Granada, Spain 3Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain *Correspondence: [email protected] (M.J. Ruiz-Magaña) and [email protected] (E.G. Olivares). Trends in Immunology 2 Trends in Immunology, Month 2025, Vol. xx, No. xx UNCORRECTED PROOF 46 dDSC, and in vivo, become rounder, secreting PRL and IGFBP-1 ( Figure 1)[ 18]. The antigenic 47 phenotype and morphology of preDSC and dDSC lines correlate with those of perivascular cells 48 and extravascular DSCs of the first-trimester decidua, respectively, as observed via confocal 49 microscopy (Table 1, Figure 1B) [16,21] and ScRNAseq [6]. Furthermore, DSC lines have a func- 50 tional pro file that seems to be equivalent to that of primary DSCs, as de fined by ScRNAseq in 51 mice and humans, including for myofibroblast-related cells [22,23]; this has also been noted during 52 angiogenesis [6,8,18], immune cell recruitment, and immunosuppression to achieve pregnancy 53 homeostasis [2,8], or to induce apoptosis [ 8,24] or tumor cell cytolysis [ 8,16]. 54 PreDSCs constitute the perivascular niche of the decidua, which is also observed in the endome- 55 trium. From this niche, the cells secrete cytokines and growth factors and interact with endothelial 56 cells that they surround, promoting angiogenesis. PreDSCs also interact with decidual immune 57 cells and the extracellular matrix, attracting peripheral blood immune cells to the decidua [ 25,26]. 58 dDSCs, located in the extravascular space, also form a niche where they crosstalk with decidual 59 immune cells, epithelial cells, and trophoblasts [27–29]. Through these homeostatic mechanisms 60 (i.e., angiogenesis, immunoregulation, and interactions with epithelial cells and trophoblasts) 61 DSCs can support embryo implantation [30–32]. 62 Decidualization induces changes in cell morphology, tissue location, as well as 63 DSC antigenic phenotypes and functions 64 Decidualization is essential for pregnancy to proceed. It is a multi-step process of differentiation 65 that affects all cells of the endometrium and decidua, but is particularly evident in DSCs as they 66 differentiate from preDSCs to dDSCs. This process involves a change in cell morphology from 67 a fibroblastic appearance to a polygonal or rounded shape, along with a change in tissue localiza- 68 tion, where preDSCs leave the perivascular niche to become extravascular dDSCs (Figure 1)[ 21]. 69 Additionally, decidualizati on also changes the antigenic p henotype of preDSCs, as dDSCs 70 downmodulate the expression of α-smooth muscle (SM)-actin, CD140b, CD146, and sushi 71 domain-containing 2 (SUSD2) (all four pericyte markers) ( Figure 1 ). Upon decidualization, 72 dDSCs in their extravascular location downregulate the expression of these pericyte molecules 73 involved in interactions with endothelial cells [ 6,16,18]. Obviously, changes that the DSCs un- 74 dergo during decidualization are accompanied by corresponding changes in function, particularly 75 in DSC immune activities: among the molecules produced by DSCs (and involved in interactions 76 with decidual immune cells), IL-15, insulin-like growth factor 1 (IGF1), CCL2, B-cell activating fac- 77 tor (BAFF)-R, and CXCL12 increase with decidualization [ 16,33–36], while CXCL9, CXCL10, 78 CXCL11, and CCL5 decrease [ 2,4]. Other molecules expressed or secreted by DSCs during b0:2 Box 1. The decidua and maternal immune response during mammalian pregnancy b1:3 Many of the mechanisms of maternal–fetal immune tolerance, although occurring in the decidua, extend their effects to the b1:4 systemic maternal immune system [98]. One of these mechanisms has been thought to be based on the T helper 1–T helper b1:5 2( T h 1–Th2) cell balance. A role of Th1 cells has been associated with spontaneous abortion, because these cells activate b1:6 cytotoxic lymphocytes– similar to the immune response in organ transplantation– which attack fetal tissues [99]. In contrast, b1:7 Th2 cells have been associated with normal pregnancy because they inhibit Th1 differentiation [100]. However, the Th1–Th2 b1:8 cell paradigm has been viewed as being too simplistic with the discovery of new subsets of Th cells [ 1]. Moreover, a report b1:9 suggested that a certain degree of inflammation along with Th1 cells, rather than being detrimental, can play a physiological b1:10 role in certain stages of normal pregnancy, such as implantation and parturition [39]. These findings support the concept that b1:11 inflammation plays a role in physiological processes [101]. Nevertheless, recent views maintain that, with the exception of the b1:12 beginning (implantation) and end of pregnancy (parturition), when inflammation and Th1 cells play a role, Th2 cells– as part of b1:13 broader type 2 immune response– are key elements in maternal–fetal tolerance during the long intermediate period of preg- b1:14 nancy. Th2 cells can block the abortigenic activity of Th1 cells during this stage, irrespective of the contribution of other Th b1:15 subsets [39,98]. The importance of a Th1–Th2 balance is exemplified by the fact that normal pregnancy ameliorates certain b1:16 Th1-mediated diseases, while increasing susceptibility to infection by intracellular pathogens (where immune defense depends b1:17 on Th1 cells) and the worsening of certain Th2-associated diseases. These observations also suggest that a Th1–Th2 balance b1:18 is not limited to the decidua, but may have a systemic effect on the immune system of pregnant women [39,98]. Trends in Immunology Trends in Immunology, Month 2025, Vol. xx, No. xx 3 Glossary Blastocyst: a structure that begins to form 5 days after oocyte fertilization in humans. Approximately 7 days later, the blastocyst undergoes implantation and becomes embedded in the endometrium. The embryo and trophoblast are derived from the blastocyst. Cellular niche: as p e c i a l i z e d microenvironment of cell–cell and cell– extracellular matrix component interactions to support the growth and differentiation of specificc e l lt y p e s . Cellular senescence: as t a t eo f cessation of cell division and secretion of proinflammatory molecules. Endometrial stromal cells (EnSC): cells of the non-pregnant endometrium that are equivalent to DSCs. During the menstrual cycle, EnSCs are also decidualized by the effects of ovarian hormones; however, if pregnancy occurs, the EnSCs continue as DSCs (Box 5). ‘Uterine stromal cells’ is a collective term for both DSCs and EnSCs. Endometriosis: presence of endometrial tissue outside the uterus, most commonly in the peritoneum and on the ovaries. This recurrent chronic inflammatory disease causes pelvic pain and infertility. Endometrium: the inner layer of the mammalian uterus. It differentiates under the effects of P4 and estrogen and becomes receptive to implantation of the blastocyst. If pregnancy occurs, the endometrium continues its differentiation (decidualization) to become the decidua. If pregnancy does not occur, this tissue is eliminated with menstruation. Graft-versus-host disease:in bone marrow transplantation, rejection of the recipient's tissue by the donor's immune cells. High endothelial venules (HEVs): specialized venules for lymphocyte migration with plump endothelial cells, which are present in secondary lymphoid organs (with the exception of the spleen). Implantation:adhesion and invasion of the endometrium by the blastocyst 7 days after fertilization in humans. Pericytes: cells that surround microvascular endothelial cells and regulate vascular structure and homeostasis. Pericytes produce angiogenic factors and exhibit contractile, chemotactic, phagocytic, and immunoregulatory activities. UNCORRECTED PR OOF 79 decidualization that contribute to maternal –fetal immune tolerance processes include HLA-G, 80 which may block dNK cell cytotoxicity, and IL-10, which promotes a type 2 immune response 81 [37]. In general, decidualization induces an immunoregulatory pro file in dDSCs [ 2,37]; a biphasic 82 process, it involves the transition of DSCs from a proin flammatory phase that is associated with 83 preDSCs, to an anti-in flammatory phase that is associated with dDSCs [ 2,38]. While the in flam- 84 matory activity of preDSCs promotes the implantation process [ 39], dDSCs – which expand dur- 85 ing the post-implantation period – contribute to the development of a type 2 immune response 86 that favors maternal –fetal immune tolerance [ 2,5,40,41]. 87 Decidualization and subpopulations of uterine stromal cells (SCs) 88 Although studies with DSC lines have provided some valuable insights into antigenic phenotypes 89 and functions, to our knowledge, this approach has not adequately identi fied the various cellular b0:2 Box 2. Immune cell composition of the human decidua b2:3 The human decidua is composed of epithelial and endothelial cells, leukocytes, and DSCs (Figure 1A). Under physiological b2:4 conditions, the leukocyte content offirst-trimester decidua is unusually high for a noninflammatory tissue (30–40% of all de- b2:5 cidual cells) [102]. The most abundant immune cells are distinctive CD56brigthQ4 CD16− NK cells: decidual NK (dNK) cells (~70% b2:6 of all decidual leukocytes in early human decidua) [103], of which three subsets have been identified [6], with their main func- b2:7 tion seeming to be the control of trophoblastic invasion and vessel development in the decidua [104,105]. Macrophages are b2:8 the next most abundant leukocyte infirst-trimester decidua (~20% of all decidual leukocytes) [106]. M1-like (proinflammatory) b2:9 and M2-like (anti-inflammatory) macrophages have been identified by ScRNAseq and mass cytometry [6,106]. T cells (~10%) b2:10 [106] include CD4+ and CD8+ T cells, along with Tregs [6]. Small populations of DC1 and DC2 dendritic cells, and group 3 b2:11 innate lymphocyte cells (ILC3s), have also been detected [ 6,106]. Two subsets of ILC3s have also been identi fied: natural b2:12 cytotoxicity receptors (NCR)+ and NCR− ILC3 [77]. The proportions of first-trimester leukocytes evolve throughout preg- b2:13 nancy. Although there are discrepancies across different publications, the general consensus is that dNK cells reach a max- b2:14 imum number in the first trimester and progressively decrease until term, while T cells steadily increase until term [ 106]. b2:15 Despite the abundance of lymphocytes, the existence of stromal cells (SCs) with immune activities, and the presence of high b2:16 endothelial venules (HEVs) [107]( Figure I) – all of which are characteristic of SLOs– the human decidua cannot be considered b2:17 an SLO. It lacks the T and B cell compartmentalization that is typical of these organs and, in addition, is a site of antigenic b2:18 capture rather than antigen presentation [108]. TrendsTrends inin ImmunologyImmunology b2:20b2:20 Figure I. Representative electron micrograph of a high endothelial venule (HEV) from a first-trimester human b2:21 decidua. Scale bar: 5 μm.b2:22 Trends in Immunology 4 Trends in Immunology, Month 2025, Vol. xx, No. xx Placenta: organ that connects the mother to the fetus. It provides oxygen and nutrients to the fetus and removes waste products. The placenta consists of two interconnected parts: the decidua, of maternal origin, and the trophoblast, of fetal origin. During physiological pregnancy in humans, the trophoblast invades the vessels of the decidua – a process controlled by decidual immune cells. Recurrent pregnancy loss (RPL):the loss of two or more consecutive pregnancies before 24 weeks of gestation. Trophoblast: fetal part of the placenta derived from the outer cell layer of the blastocyst. Trophoblast cells are involved in embryo nourishment and implantation. They also invade the decidua and replace blood vessel endothelial cells. This process ensures adequate blood supply during pregnancy. Type 2 immune response: adaptive immune response centered on differentiated Th2 cells and the secretion of a distinct repertoire of cytokines, including IL-4, IL-5, and IL-13. The type 2i m m u n er e s p o n s ep r o m o t e s antihelminthic immunity, suppresses type 1-driven immune responses, and regulates wound repair and tissue regeneration. UNCORRECTED PROOF 90 steps in the decidualization process [ 16]. In contrast, ScRNAseq technology has facilitated a 91 more precise analysis of cellular pathway(s) in the differentiation process, as well as of cell –cell 92 communications [ 25]. This technology has been used to st udy decidualization in human and 93 mouse endometrium and decidua, where differe nt numbers of subpopulations or clusters of t1:1 Table 1. Antigen expression by human bone marrow MSC, preDSC, and preFDC lines obtained and t1:2 maintained in equivalent culture conditions, as determined by flow cytometry [ 16,18–20,35,76,112]a t1:3 Antigenb BM-MSCs preDSCs preFDCs t1:4 CD10c +++ t1:5 CD13 + + + t1:6 CD15 ––– t1:7 CD19d –– ND t1:8 CD29 + + + t1:9 CD31 ––– t1:10 CD34d ––– t1:11 CD44 + + + t1:12 CD45d ––– t1:13 CD62P –– ND t1:14 CD73d +++ t1:15 CD90d +++ t1:16 CD105d +++ t1:17 CD140be,f,g ND + + t1:18 CD146e,f ++ – t1:19 α-SM actinf +++ t1:20 BAFFh,i – ++ t1:21 CXCL12 ND + + t1:22 CXCL13h – ++ t1:23 Cytokeratin ND – ND t1:24 HLA-DRd ––– t1:25 HLA-G – +g ND t1:26 ICAM-1g +++ t1:27 MFGE8h ND + + t1:28 Nestin + + + t1:29 Podoplanin + + + t1:30 Prolactinh +++ t1:31 STRO-1f +++ t1:32 SUSD2e,f ++N D t1:33 VCAM-1g +++ t1:34 aFrom [21], with permission. t1:35 b BM-MSCs, bone marrow mesenchymal stem cells from bone marrow aspirates; ND, not determined; preFDCs, precursors t1:36 of follicular dendritic cells from tonsillectomies. t1:37 cEndometrial stomal cell marker [ 113]. t1:38 d Antigens meeting the minimal criteria for identi fication as mesenchymal stem cells [ 50]. t1:39 eEndometrial mesenchymal stem cell marker [ 51]. t1:40 fPericyte marker [ 114]. t1:41 gImmunofibroblast marker [ 69,70]. t1:42 hFollicular dendritic cell marker [ 115]. t1:43 iQ3 Under decidualization conditions. Trends in Immunology Trends in Immunology, Month 2025, Vol. xx, No. xx 5 UNCORRECTED PR OOF 94 EnSCs or DSCs (uterine SCs) have been identi fied [7,25–29]. Stemming from the gene expres- 95 sion profiles of these cells, the functionality of each cluster can be inferred, and the interactions 96 of uterine SCs with other cells (i.e., immune, end othelial, epithelial, an d trophoblast cells) can 97 be de fined in their respective cellular niches [7,25–29]. Among the many DSC interactions 98 and functions identi fied thus far, here we focus speci fically on immune responses. Although 99 some differences in the results obtained have been noted across ScRNAseq studies, several 100 trends are consistently observed: (i) a gradual increase in the expression of the decidualization 101 markers PRL and IGFBP1 in the DSC pathway [ 6,8,10,42], (ii) the presence of clusters involved 102 in immune responses [8,22,43], and (iii) a decrease in these clusters as decidualization progresses 103 [6]; these results are consistent with those reported in DSC lines [2]. The presence of human DSC 104 clusters that are enriched for inflammation-associated genes, termed inflammatory DSCs (iDSCs) 105 [22], and of CD24+ DSCs [43], has been observed. Similarly, in mice, a cluster of DSCs that express 106 genes related to immune responses was identi fied and named immune-featured DSCs (also 107 iDSCs) [8]. ScRNAseq technology has also implicated human and mouse DSCs during parturition 108 [9–12]. In pathologies involving altered decidualization, such as endometriosis, antiphospholipid 109 syndrome, recurrent pregnancy loss (RPL), and pre-eclampsia [44–47], an immunoactivating 110 response seems to predominate and can negatively affect pregnancy [2,38]( Box 3). 111 Decidualization, senescent uterine SCs, and dNK cell embryonic biosensing 112 Decidualization of human EnSCs progres ses along a continuous trajectory towards cellular 113 senescence , resulting in the formation of a subpopu lation of senescent EnSCs (snEnSCs). 114 These are P4-resistant cells that express abundant extracellular matrix proteins, secrete proin- 115 flammatory cytokines and chemokines, and also induce secondary senescence in neighboring 116 EnSCs, impairing interactions with trophoblast cells and hindering subsequent embryo implanta- 117 tion [ 48]. Experimental evidence suggests that under normal conditions, endometrial NK cells b0:2 Box 3. Uterine stromal cell (SC) pathology b3:3 ScRNAseq has indicated the involvement of uterine SC subpopulations in recurrent pregnancy loss (RPL). In general, an b3:4 increase in SC clusters with enriched expression of genes important in cell apoptosis and senescence [13,28], as well as in b3:5 immune responses [ 22,43,47], has been observed. In addition, interactions of DSCs with in flammatory decidual macro- b3:6 phages, as well as with dNK cells, have been demonstrated [ 22]. Other work shows that DSCs from RPL fail to induce b3:7 the differentiation of naïve CD4 + T cells into regulatory T cells (Tregs) [ 43]. A relevant finding in RPL was that there was b3:8 defective DSC decidualization [ 28]. Moreover, a pre-pregnancy study assessing the endometrium of patients with RPL b3:9 showed an increase in snEnSCs, along with a de ficiency in endometrial NK cells, relative to non-RPL controls; this sup- b3:10 ported the notion that the failure of endometrial NK cells to eliminate snEnSCs can lead to miscarriage [ 13]. In a mouse b3:11 model of immune-based RPL, a DSC cluster enriched with chemokine genes was detected, whereas vascularization of b3:12 a second DSC cluster and cytolytic functions of a third DSC cluster were inhibited. This led to abnormal immune cell b3:13 enrichment and in flammation, along with impaired vascularization and cytolysis, ultimately resulting in pregnancy loss b3:14 [8]. Similar findings have been observed in other obstetrical pathologies such as preterm labor, defined in humans as labor b3:15 occurring between 20 and 37 weeks of gestation. In a mouse model of preterm labor, DSCs were enriched for genes b3:16 related to leukocyte migration and chemotaxis [ 109]. In human preterm labor, differences in gene expression compared b3:17 to normal parturition have also been detected in DSCs and certain immune cells [ 110]. b3:18 Ectopic foci in endometriosis consist of endometrial tissue and leukocytes, which trigger a local in flammatory response b3:19 [92]. In ectopic areas, EnSCs may attract and interact with leukocytes (mainly macrophages), thereby contributing to b3:20 the development of endometriotic lesions. Interactions between EnSCs and macrophages seem to be essential for the b3:21 maintenance of these foci [ 26,94]. Accordingly, ScRNAseq technology showed that two clusters of decidualized EnSCs b3:22 along with endometrial M1-like and M2-like macrophage populations were enriched for the expression of genes associ- b3:23 ated with endometriosis risk variants. These results suggested dysregulated EnSC –macrophage homeostasis, potentially b3:24 contributing to the characteristic in flammation seen in endometriosis [ 26,94]. Other single-cell studies have also reported b3:25 EnSC and immune cell dysregulation in endometriosis (e.g., EnSC clusters with enriched expression of genes important for b3:26 immune responses and senescence), as well as a reduction in endometrial NK cell numbers compared to controls b3:27 [45,46,111]. The association of increased EnSC senescence with decreased endometrial NK cell populations may indicate b3:28 an impaired ability of these latter cells to clear senescent EnSCs (SNEnSCs), which in turn might contribute to the in flam- b3:29 mation associated with endometriosis [ 13,45,46]. Trends in Immunology 6 Trends in Immunology, Month 2025, Vol. xx, No. xx UNCORRECTED PROOF 138138138138138138138138138138138138138138138138138138 eliminate these snEnSCs by granule exocytosis to limit the potentially deleterious effects of exces- 139 sive in flammation induced by snEnSCs in a future pregnancy [ 13,49]. Moreover, this process 140 seems to be part of a broader mechanism of embryo biosensing by dNK cells. In vitro studies 141 have demonstrated that low-quality embryos secrete substances (such as high-molecular- 142 weight hyaluronic acid) that inhibit the cytotoxic activity of endometrial NK cells on snEnSCs. 143 This inhibition may increase the number of snEnSCs, promoting an excessively in flammatory en- 144 vironment that may impede pregnancy [ 31]. Senescent DSCs have also been found in human 145 pregnancy, where DSC subpopulations exhibit high expression of genes related to cell apoptosis 146 and senescence. This suggests that a similar mechanism for the elimination of senescent DSCs 147 by dNK cells might also operate during normal pregnancy [ 28,30]( Box 3). 148 DSCs are related to mesenchymal stromal/stem cells (MSCs) 149 Human preDSC lines meet the minimal criteria established by the International Society for Cellular 150 Therapy to define human MSCs [ 50], namely, expression of CD73, CD90, and CD105, and lack 151 of expression of CD19, CD34, CD45, and HLA-DR (Table 1), adherence to plastic culture dishes, 152 and the capacity to differentiate into adipocytes, osteoblasts, and chondrocytes [ 19]. In addition, 153 preDSCs express CD140b, CD146, and SUSD2, w hich are markers of endometrial MSCs 154 (eMSCs) that can be detected in the non-pregnant endometrium ( Table 1 )[ 21]. PreDSCs and 155 eMSCs share several characteristics, including perivascular localization, an antigenic phenotype, 156 a clonogenic and self-renewal potential, as well as the capacity to differentiate into mesenchymal 157 lineages in vitro [19,21,51]. Like MSCs, DSCs also show immunoregulatory activities both in vitro 158 and in vivo; furthermore, they have shown certain therapeutic effects for some immune-related 159 diseases [ 19,52,53]( Box 4 ). The similarity between preDSCs and MSCs suggests that DSCs 160 or their endometrial counterparts, EnSCs, might potentially originate from bone marrow MSCs. 161 These latter cells may colonize the endometrium and decidua, where the molecular microenviron- 162 ment might enable them to fully acquire the characteristics of uterine SCs [ 20,35]. Several lines of 163 evidence support this possibility. Bone marrow-derived MSCs can differentiate in vitro via the 164 DSC pathway [54]. Donor-derived EnSCs have also been identi fied in women having undergone 165 bone marrow transplantation [ 55] – a finding that was also con firmed in mouse models [ 56,57] 166 (Box 5). Additionally, in both mice and humans, endometrial inflammation and pregnancy can mo- 167 bilize bone marrow MSCs into circulation, and bone marrow-derived cells, likely stemming from 168 MSCs, have been shown to colonize the uterus, proliferate, and differentiate into SCs, thus con- 169 tributing to the regeneration of the endometrium [ 58–60]. This migration is mediated by CXCL12 170 [61]. Furthermore, transcriptomic analysis of human EnSCs, demonstrated similarities between 171 these cells and MSCs [62]. Experimental evidence suggested that MSCs and pericytes likely con- 172 stitute the same population, although this remains to be demonstrated [ 63]. Accordingly, like b0:2 Box 4. Decidual stromal cells (SCs) and endometrial SCs may be the same cells under different contexts b4:3 and with different decidualization capacities b4:4 Although DSC and EnSC can be considered the same cell type under different physiological situations (pregnant endome- b4:5 trium or decidua, and non-pregnant endometrium, respectively), there is considerable confusion in the literature regarding b4:6 their nomenclature. Some authors refer to EnSCs as non-decidualized cells and to DSCs as decidualized cells. These b4:7 terms do not accurately reflect the location and differentiation status of these cells, given that the process of decidualization b4:8 takes place in both the endometrium and the decidua, and therefore there are precursor and differentiated cells in both the b4:9 endometrium (preEnSCs and dEnSCs) and the decidua (preDSCs and dDSCs) [ 26]. Furthermore, DSCs have a greater b4:10 capacity for decidualization than EnSCs, as evidenced by the characteristics and molecules associated with the process b4:11 of decidualization: secretion of PRL and IL15, round morphology, and apoptosis [ 6,7,35]. These differences are probably b4:12 due to the different environments (non-pregnant endometrium vs. pregnant endometrium) in which EnSCs and DSCs are b4:13 found, respectively, making it necessary to clearly differentiate one cell type from the other [ 21,35]. The fact that it is the b4:14 decidua and not the endometrium that f aces the allogenic challenge of the trop hoblast suggests that immunological b4:15 and cellular mechanisms may occur in the decidua that determine the functional differences between SCs in these b4:16 two tissues. Trends in Immunology Trends in Immunology, Month 2025, Vol. xx, No. xx 7 UNCORRECTED PR OOF 186186186186186186186186186186186186186186 pericytes, preDSCs express pericyte markers, are detected in perivascular locations, and exhibit 187 cell contractility [ 18]. In summary, we posit that DSCs can be considered cells of mesenchymal 188 origin (i.e., uterine fibroblasts) that perform immune functions to support pregnancy. 189 DSCs as specialized fibroblasts 190 Although there seem to be no fibroblast-specific markers, antigens such as CD140b, podoplanin 191 (PDPN), CD90, and α-SMA are commonly associated with fibroblasts. These cells are also char- 192 acterized by the absence of molecules associat ed with other lineages, such as endothelial 193 (CD31), epithelial (EPCAM), or hematopoietic (CD45) cells [ 64]. Of note, human preDSCs exhibit 194 this antigenic profile (Table 1)[ 21]. Fibroblasts constitute a heterogeneous population that is dif- 195 ficult to classify yet which is widely distributed throughout the mammalian organism. These cells 196 are not only involved in tissue repair and organization, but also perform immunoregulatory func- 197 tions [65]. One of the best studied types of fibroblasts are those found in secondary lymphoid or- 198 gans (SLOs), known as fibroblastic reticular cells (FRCs), which display distinctive characteristics. 199 These cells interact with immune cells, facilitate their differentiation and survival, regulate some of 200 their responses, and stimulate the activation of an adaptive immune response to prevent the dis- 201 semination of pathogens in the body [66]. Classically, three major FRC subpopulations have been 202 well defined: follicular dendritic cells (FDCs), located in the B-zone of lymphoid follicles; T-zone re- 203 ticular cells (TRCs; in the parafollicular region); and marginal reticular cells (in the marginal zone). 204 Recently, additional stromal subpopulations were identi fied via ScRNAseq [ 67]. Fibroblasts dis- 205 tributed throughout the rest of the body are referred to as non-SLO fibroblasts or tissue fibro- 206 blasts. There is considerable evidence that these fibroblasts are also actively involved in the 207 immune system [65]. In fact, in local immune responses such as infection, chronic in flammation, 208 transplantation, or cancer, proin flammatory cytokines can activate tissue fibroblasts, causing 209 them to acquire immune characteristics, and have been termed immuno fibroblasts. These cells 210 are also responsible for the formation of TLSs at sites of chronic in flammation (see later) 211 [64,65,68,69]. 212 Since the decidua is not an SLO ( Box 2), DSCs should be classi fied in the group of non-SLO fi- 213 broblasts. Within this group, preDSCs are comparable to immuno fibroblasts. Murine and 214 human immuno fibroblasts express PDPN, CD140b, IC AM-1, VCAM-1, and RANK-L, as well 215 as CXCL10, CXCL13, CCL5, CCL19, and BAFF [ 69,70], all of which are also expressed by 216 preDSCs ( Table 1 )[ 2,21] (T. Llorca, doctoral thesis, University of Granada, 2024Q9 ). Like tissue b0:2 Box 5. Decidual stromal cell (SC) therapy b5:3 Although the therapeutic effects of bone marrow MSCs are promising because of their immunoregulatory properties, the b5:4 results of clinical trials have been inconsistent. This may be due to the lack of a standardized method for sample collection, b5:5 and the possibility that cell preparations contain mixtures of different subpopulations with different activities. In addition, b5:6 in vitro expansion is required for clinical use, and culture procedures may induce cell differentiation, leading to the loss b5:7 of stem properties [ 119]. Furthermore, bone marrow aspiration is a painful procedure, prompting interest in alternative b5:8 tissues such as the placenta or menstrual blood, where SCs are more easily accessible. DSCs have been proposed as b5:9 an alternative to MSCs, not only because their immunoregulatory activities suggest a therapeutic potential – especially b5:10 in Th1 cell-mediated diseases [ 2] – but also because they can be obtained painlessly from term placentas [ 89]. The b5:11 therapeutic effect of DSCs [3] has been demonstrated in several murine models and human clinical trials. In a mouse model b5:12 of Th1-mediated recurrent miscarriage (RPL) using female CBA/J mice mated with male DBA/2 mice – characterized by a b5:13 high rate of embryonic resorption – inoculation of human DSCs into pregnant CBA/J mice signi ficantly reduced the abor- b5:14 tion rate [19,53]. Other reports also documented the bene ficial effects of human DSCs on steroid-refractory graft-versus- b5:15 host disease (a Th1-mediated process) in humans (i.e., a greater therapeutic ef ficacy than bone marrow MSCs) [ 52,120]. b5:16 This finding suggests that DSCs can be a potentially important component of cell-based therapies to treat certain immune- b5:17 mediated diseases. In fact, DSCs have also shown promising results for the treatment of coronavirus disease b5:18 2019 (COVID-19)-induced acute respiratory distress syndrome [ 121]. EnSCs – DSC-equivalent cells in the non-pregnant b5:19 endometrium – have also demonstrated numerous therapeutic effects. In this regard, EnSCs derived from menstrual blood b5:20 are a potential noninvasive, easily obtainable source of these cells, which might be used in autologous therapies [ 122]. Trends in Immunology 8 Trends in Immunology, Month 2025, Vol. xx, No. xx UNCORRECTED PROOF 217 fibroblasts that undergo differentiation into immuno fibroblasts in response to local immune 218 signals, MSC-related preDSC progenitors, when exposed to the decidua-associated immune 219 response (Box 1), may also differentiate into a form of immunofibroblast. Indeed, tissue fibroblasts 220 in mice differentiate into immuno fibroblasts under the effect of IL-13 and IL-22 [ 69]. In human 221 decidua, IL-13 is produced by dNK cells [ 41], and IL-22 is produced by DSCs, dNK cells [ 71], 222 and CD4+ T cells [ 72]. 223 Reports suggest that immuno fibroblasts are phenotypically an d functionally similar to FRCs 224 [69,70]. Thus, DSCs also seem to be related to FRCs, particularly to FDCs. Several lines of 225 evidence support these relationships. Regarding the origin of FRCs, during human and mouse 226 embryonic development, FRCs are derived from l ymphoid tissue organizer (LTo) cells, which 227 are located in perivascular sites and are related to MSCs. LTo cells interact with lymphoid tissue 228 inducer (LTi) cells, which are a distinctive type of innate lymphocyte cell [ 73]. This LTo –LTi inter- 229 action contributes to attracting B and T lymphocytes, as well as DCs, into the SLO primordium, 230 and to further differentiate into LTo cells, which then express adhesion molecules ICAM-1 and 231 VCAM-1, thus contributing to the organization of lymphoid tissues [74]. In adults, FRC precursors 232 are also related to perivascular cells or pericytes [75,76]. Like the embryonic LTi–LTo interaction in 233 the SLO primordium for lymph node formation [73], decidual group 3 innate lymphoid cells (ILC3) 234 interact with DSCs. This interaction increases the expression of adhesion molecules ICAM-1 and 235 VCAM-1 on DSCs, suggesting that these cells are involved in leukocyte attraction and, presum- 236 ably, tissue remodeling [77]. In addition, there is evidence of phenotypic and functional similarities 237 between DSCs and FDCs, as summarized in Tables 1 and 2 [18–20,75,78]. Lastly, the posited 238 relationship between DSCs and FDCs is supported by transcriptomic analysis of human FDCs, 239 EnSCs, and MSCs, con firming that FDCs and EnSCs are closely related and that both cell 240 types are also related to MSCs [ 62]. Despite their similarities, DSCs are not the same as FDCs; 241 these two types of cells are comparable but exhibit characteristic differences [ 21,115]. t2:1 Table 2. Comparison of phenotypic and functional characteristics of human preDSCs and preFDCs a t2:2 Criteria considered preDSCs preFDCs Refs t2:3 Antigenic phenotype (see Table 1 ) t2:4 -Endometrial stromal cell marker t2:5 -MSC/pericyte markers t2:6 -eMSC markers t2:7 -FDC markers + + + + + + + + [16,18–20,35,76,112] t2:8 Perivascular location of t2:9 CD140b+ MFGE8+ precursors + (Decidua) + (Secondary lymphoid organs) [18,75,76] t2:10 Mesenchymal differentiation into adipocytes, t2:11 osteoblasts, and chondrocytes ++ [ 19,50,76,116] t2:12 Decidual differentiation into prolactin-secreting cells + + [ 20] t2:13 Inhibition of B cell apoptosis + + [ 18,20,76] t2:14 Cell contractility + + [ 18,112,117]b t2:15 Chemotactic activity + + [ 2,16,18,76] t2:16 In vitro immunoregulatory activity + + [ 20,76,112,116] t2:17 Hematopoietic cell supportive activity NK cells B cells [ 20,76,112,118] t2:18 Presence in ectopic sites + c +d [69,92] t2:19 aFrom [21] with permission. t2:20 b TRCs are also contractile cells. t2:21 cInduced by endometrial stromal cells. t2:22 d FDC-like cells from immuno fibroblasts. Trends in Immunology Trends in Immunology, Month 2025, Vol. xx, No. xx 9 UNCORRECTED PR OOF 242 DSCs set up, support, and suppress decidual immune responses 243 According to one report, fibroblasts can help initiate, govern, and moderate certain immune re- 244 sponses [ 64]. Similarly, the general functions of FRCs and non-SLO fibroblasts have been re- 245 ported to set up, support, and suppress immune responses [ 65]. For setup, fibroblasts secrete 246 chemokines that attract immune cells, thereby helping to organize SLOs (in the case of FRCs), 247 or TLSs (in the case of non-SLO fibroblasts in chronic inflammation) [65]. For support, fibroblasts 248 secrete antiapoptotic factors and induce immune cell differentiation [ 65]. For suppression, fibro- 249 blasts can regulate immune respon ses to mediate immune tolerance [ 65]. FRCs display their 250 functional activities mainly on T and B lymphocytes, whereas non-SLO fibroblasts have a more 251 evident regulatory effect on innate immune cells [ 65]. 252 Like FRCs and non-SLO fibroblasts, DSCs can perform the general functions of fibroblasts, set- 253 ting up, supporting, and suppressing an immune response ( Figure 2). For setup, DSCs partici- 254 pate in the recruitment of peripheral blood NK (pbNK) cells by secreting chemokines CX3CL1, 255 CXCL10, and CXCL12 [ 79]. PreDSCs secrete CXCL9, CXCL1 0, and CXCL11, which attract 256 Th1 and Tc lymphocytes from peripheral blood [ 2]. Although these T cel ls are potentially 257 abortigenic, they may be important in the defense against infection and during the in flammatory 258 phase that is associated with implantation [ 39]. Nevertheless, Th1 and Tc chemotaxis can be 259 controlled by dDSCs during the anti-inflammatory phase of decidualization [2] (see later). For sup- 260 port, DSCs secrete antiapoptotic factors affecting dNK, pbNK, and peripheral blood T cells [ 16]. 261 DSCs also induce differentiation from pbNK to d NK cells through the effect of transforming 262 growth factor β1( T G F -β1 ) ,I L - 1 5 ,I L - 1 8 ,a n dI L - 2 4[80–82]. Additionally, DSCs can interact 263 with decidual CD34 +CD45+ hematopoietic progenitor cells and induce their differentiation into 264 dNK cells [ 80,83]. These two possible origins of dNK cells may not be mutually exclusive, be- 265 cause different subsets of dNKs have been identi fied [6]. Upon secreting macrophage colony- 266 stimulating factor, DSCs also favor the differentiation of monocytes into M2-like (anti-inflammatory) 267 macrophages, which are predominant in human decidua [84]. For suppression, DSCs drive dNK to 268 a non-cytotoxic state by producing prostaglandin E 2 (PGE2), indoleamine 2 3-dioxygenase (IDO) 269 [85], TGF-β [81], IL-24 [ 82], IL-33 [ 41], and IGF1 [ 36]. Decidual dendritic cells (dDCs) are main- 270 tained in an immature state by the effects of PGE 2, IDO, and macrophage inhibitory cytokine-1 271 (MIC-1) that are secreted by DSCs [ 85,86]. Immature DCs exhibit tolerogenic activity; indeed, 272 first-trimester dDCs produce little IL-12, promote differentiation toward Th2 cells, and prevent 273 the activation of abortive Th1 and Tc cells [87]. dDCs also induce regulatory T cell (Treg) by secret- 274 ing TGF-β1[ 88]. Mouse DSCs undergo epigenetic silencing of T cell attracting in flammatory che- 275 mokine genes ( CXCL9, CXCL10, CXCL11, and CCL5), which prevent the arrival of harmful Th1 276 and Tc cells to the decidua, and this effect seems to be induced by decidualization [4]. A similar ef- 277 fect has been observed in human dDSCs [ 2] (T. Llorca, doctoral thesis, University of Granada, 278 2024). Furthermore, dDSCs inhibit the expression of IFNG and TNFA by activated T lymphocytes 279 and secrete low-molecular-weight thermostable factor(s) that inhibits Th1 and Tc chemotaxis 280 [T cell chemotaxis-inhibiting factor (TCIF)] [ 2]. Additionally, DSCs induce differentiation into Tregs 281 from peripheral blood T cells through the action of IDO [ 89] and TGF-β [84], and from decidual T 282 cells through the action of IL-33 [ 5]. By secreting CCL2 and IL-33, DSCs enhance Th2 cytokine 283 production and inhibit Th1 cytokine secretion [ 40,41]. In general, DSCs interact with different im- 284 mune cells of the decidua, establishing the predominance of a type 2 immune response that favors 285 immune tolerance to fetal tissues [2,5,40,41]. 286 Ectopic sites: TLSs and endometriosis 287 In addition to the three criteria for the general immune functions of fibroblasts, a fourth criterion 288 can be posited: the presence of these cells in ectopic sites. Under chronic in flammation (e.g., au- 289 toimmunity, infection, and cancer), tissue fibroblasts differentiate into immuno fibroblasts that Trends in Immunology 10 Trends in Immunology, Month 2025, Vol. xx, No. xx UNCORRECTED PROOF 290 phenotypically and functio nally resemble FRCs and are capable of organizing TLSs 291 [64,65,68,69]. The cellular organization of these TLSs is similar to that of SLOs, with the presence 292 of TRC- and FDC-like cells, along with high endothelial venules (HEVs) [90]. Although DSCs 293 can be found in ectopic locations (deciduosis), it is much more common to find their endometrial 294 counterparts, EnSCs, in ectopic sites during endometriosis [91]. Endometriotic foci are compara- 295 ble to TLSs, because both types of structure constitute ectopic foci that are induced by SCs with 296 immunofibroblasts characteristics [ 21,69,92] (T. Llorca, doctoral thesis, University of Granada, 297 2024) and both harbor HEVs [15,90,93]. Despite these similarities, their corresponding cellular or- 298 ganizations differ. TLSs contain more or less well-de fined B and T cell areas [ 90], whereas such 299 areas are not commonly detected during endometriosis, and a high proportion of macrophages 300 and neutrophils are found instead [26,94,95]. These differences are likely due to the distinct types 301 of associated SCs and chemokines produced in each case. TLS-associated FRC-like cells are TrendsTrends inin ImmunologyImmunology Figure 2. Effects of decidual stromal cells (DSCs) on mammalian immune responses. (A) DSCs are involved in the setup, support, and suppression of decidual NK (dNK) cells (decreased cytotoxicity). The relevant molecules and pathways implicated are shown. (B) The cartoon depicts the immunoregulatory effects of DSCs on T cell subsets [Th1, Th2, and regulatory T cells (Tregs)]. The relevant molecules and pathways implicated are shown. Abbreviations: dDC, decidual dendritic cells; IDO, indoleamine 2 3-dioxygenase; IGF1, insulin-like growth factor 1; MIC-1, macrophage inhibitory cytokine-1; pbNK, peripheral blood NK; PGE 2,p r o s t a g l a n d i nE 2 ;T C I F ,Tc e l l chemotaxis-inhibiting factor; TGF- β1, transforming growth factor β1. Figure created with BioRender.com. Trends in Immunology Trends in Immunology, Month 2025, Vol. xx, No. xx 11 UNCORRECTED PR OOF 302 mainly involved in lymphocyte attraction and organization, whereas EnSCs mainly attract macro- 303 phages and neutrophils [ 26,94,95]. A certain study showed that injection of FRCs induced TLSs 304 in mice [96]; other work showed that injection of human EnSCs in mice generated endometriosis- 305 like nodules. The presence of human EnSCs along with murine macrophages and neutrophils in 306 these nodules demonstrated the chemotactic action of human EnSCs on these leukocytes during 307 nodule formation [97]. However, although endometriosis originates from a dysregulated interac- 308 tion between EnSCs and macrophages [ 26,94], the chemokines produced as a result of this in- 309 teraction may additionally attract lymphocytes [15]. In related findings, TLSs have been observed 310 in some endometriosis lesions, which may suggest lymphoid formation in areas of chronic inflam- 311 mation. Therefore, the formation of TLSs in endometriotic lesions might not be a driver for these 312 lesions, but rather, a consequence of a persistent in flammatory response [ 15,93]. 313 Concluding remarks 314 DSCs and EnSCs (uterine SCs) seem to be the same cells under different physiological contexts: 315 non-pregnancy and pregnancy, respectively. The former are immunologically challenged by the 316 fetal tissue. DSCs can be regarded as tissue-specific fibroblasts, because they share phenotypic 317 and functional similarities with fibroblasts found in immunologically active tissues, particularly re- 318 garding immune functions. Thus, both types of cells can set up, support, and suppress immune 319 responses. Additionally, both fibroblasts and DSCs are involved in the formation of ectopic foci, 320 with fibroblasts contributing to the development of TLSs, while EnSCs (i.e., the endometrial coun- 321 terparts of DSCs) are involved in the appearance of endometriosis. A careful review of the relation- 322 ships between uterine SCs and fibroblasts, along with the identi fication of shared functions and 323 molecules important for these functions, may offer valuable insights into the physiology of SC in- 324 teractions with the immune system (see Outstanding questions). In addition, these analyses may 325 lead to the identi fication of putative therapeutic targets to treat diseases associated with these 326 cells, during pregnancy or non-pregnancy. 327 Acknowledgments 328 We thank K. Shashok for editing the use of English in this manuscript. Financial support was provided byQ10 Proyectos de I+D+I 329 through the Programa Operativo Feder Andaluc ı a (Grant B-CTS-228-UGR20). 330 Declaration of interests 331 The authors declare no con flicts of interest. 332 References 335 1. Moffett, A. and Shreeve, N. (2022) Local immune recognition of 336 trophoblast in early human pregnancy: controversies and ques- 337 tions. Nat. Rev. Immunol. 23, 222–235 338 2. Llorca, T. et al. (2023) Decidualized human decidual stromal 339 cells inhibit chemotaxis of activated T cells: a potential mecha- 340 nism of maternal-fetal immune tolerance. Front. Immunol. 14, 341 1223539 342 3. Na, H. et al. (2024) The IL-6 signaling pathway contributes 343 critically to the immunomodulatory mechanism of human 344 decidua-derived mesenchymal stromal cells. iScience 27, 345 109783 346 4. Nancy, P. et al. (2012) Chemokine gene silencing in decidual 347 stromal cells limits T cell access to the maternal-fetal interface. 348 Science 336, 1317–1321 349 5. Valero-Pacheco, N. et al. (2022) Maternal IL-33 critically regu- 350 lates tissue remodeling and type 2 immune responses in the 351 uterus during early pregnancy in mice. Proc. Natl. Acad. Sci. 352 U. S. A. 119, e2123267119 353 6. Vento-Tormo, R. et al. (2018) Single-cell reconstruction of the 354 early maternal-fetal interface in humans. Nature 563, 347–353 355 7. Wang, W. et al. (2020) Single-cell transcriptomic atlas of the 356 human endometrium during the menstrual cycle. Nat. Med. 357 26, 1644–1653 3588. Yang, M. et al. (2023) Spatiotemporal insight into early preg- 359nancy governed by immune-featured stromal cells. Cell 186, 3604271–4288.e24 3619. Huang, J. et al. (2020) Single-cell transcriptomics analysis 362showing functional heterogeneity in decidual stromal cells dur- 363ing labor. J. Investig. Med. 69, 851–856 36410. Huang, J. et al. (2021) Single-cell RNA sequencing reveals het- 365erogeneity and differential expression of decidual tissues during 366the peripartum period. Cell Prolif. 54, e12967 36711. Zhao, H. et al. (2023) Stromal cells-speci fic retinoic acid deter- 368mines parturition timing at single-cell and spatial-temporal reso- 369lution. iScience 26, 107796 37012. Garcia-Flores, V. et al. (2024) Deciphering maternal-fetal cross- 371talk in the human placenta during parturition using single-cell 372RNA sequencing. Sci. Transl. Med. 16, eadh8335 37313. Lucas, E.S. et al. (2020) Recurrent pregnancy loss is associated 374with a pro-senescent decidual response during the peri- 375implantation window. Commun. Biol. 3, 37 37614. Sakabe, N.J. et al. (2020) Transcriptome and regulatory maps 377of decidua-derived stromal cells inform gene discovery in pre- 378term birth. Sci. Adv. 6, eabc8696 37915. Tan, Y. et al. (2022) Single-cell analysis of endometriosis 380reveals a coordinated transcriptional programme driving Trends in Immunology 12 Trends in Immunology, Month 2025, Vol. xx, No. xx Outstanding questions Is each DSC differentiation stage asso- ciated with a different state of function- ality? Although ScRNAseq makes it possible to identify different types of DSCs, their differentiation stages, and gene expression pro files from which functionality might be inferred, the rela- tionship between different stages of dif- ferentiation and the functions of DSCs remains to be clearly established. Does decidualization increase the immunoregulatory activity of DSCs? Decidualization increases the expression and secretion of DSC molecules with im- munoregulatory activity which seems to support this possibility. However, most functional studies do not distinguish be- tween non-decidualized and decidualized DSCs; therefore, further research is warranted. Are decidualized DSCs more suitable than non-decidualized DSCs for the treatment of certain immune-related diseases? If decidualization increases the immunoregulatory activity of DSCs, this might be the case. Given that DSCs can promote a type 2 immune re- sponse and that decidualization can favor this response, decidualized DSCs might have a therapeutic effect in Th1-mediated diseases. To date, DSCs have been observed to have a therapeutic effect on graft-versus-host disease in humans; it remains to be de- termined whether this effect is en- hanced by treatment with decidualized DSCs. Like FRCs, are DSCs involved in tissue remodeling? The presence of decidual ILC3 cells, which interact with DSCs and increase ICAM-1 and VCAM-1 ex- pression in a manner similar to the LTo–LTi interaction in the SLO primor- dium, seems to suggest this, but more research is needed. Are there common molecules expressed by DSCs and fibroblasts of immunologically active tissues that might serve as targets in the treatment of diseases associated with these cell types? Could blocking these molecules prevent the formation of TLSs and thus help ameliorate the clinical course of certain autoimmune diseases? Could blockade prevent the formation of ectopic foci in endometriosis? UNCORRECTED PROOF 381 immunotolerance and angiogenesis across eutopic and ectopic 382 tissues. Nat. Cell Biol. 24, 1306–1318 383 16. Ruiz-Magana, M.J. et al. (2021) Decidualization modulates the 384 mesenchymal stromal/stem cell and pericyte characteristics of 385 human decidual stromal cells. Effects on antigen expression, 386 chemotactic activity on monocytes and antitumoral activity. 387 J. Reprod. Immunol. 145, 103326 388 17. Richards, R.G. et al. (1995) Fibroblast cells from term human 389 decidua closely resemble endometrial stromal cells: induction 390 of prolactin and insulin-like growth factor binding protein-1 391 expression. Biol. Reprod. 52, 609–615 392 18. Munoz-Fernandez, R. et al. (2018) Human predecidual stromal 393 cells have distinctive characteristics of pericytes: cell contractil- 394 ity, chemotactic activity, and expression of pericyte markers 395 and angiogenic factors. Placenta 61, 39–47 396 19. Munoz-Fernandez, R. et al. (2019) Human predecidual stromal 397 cells are mesenchymal stromal/stem cells and have a therapeu- 398 tic effect in an immune-based mouse model of recurrent spon- 399 taneous abortion. Stem Cell Res Ther 10, 177 400 20. Munoz-Fernandez, R. et al. (2012) Human decidual stromal 401 cells secrete C-X-C motif chemokine 13, express B cell- 402 activating factor and rescue B lymphocytes from apoptosis: 403 distinctive characteristics of follicular dendritic cells. Hum. 404 Reprod. 27, 2775–2784 405 21. Ruiz-Magana, M.J. et al. (2022) Stromal cells of the endome- 406 trium and decidua: in search of a name and an identity. Biol. 407 Reprod. 107, 1166–1176 408 22. Bao, S. et al. (2023) Single-cell pro filing reveals mechanisms of 409 uncontrolled inflammation and glycolysis in decidual stromal cell 410 subtypes in recurrent miscarriage. Hum. Reprod. 38, 57–74 411 23. Oliver, C. et al. (1999) Human decidual stromal cells express 412 alpha-smooth muscle actin and show ultrastructural similarities 413 with myofibroblasts. Hum. Reprod. 14, 1599–1605 414 24. Leno-Duran, E. et al. (2014) Human decidual stromal cells 415 secrete soluble pro-apoptotic factors during decidualization in 416 a cAMP-dependent manner. Hum. Reprod. 29, 2269–2277 417 25. He, J.P. et al. (2021) Identi fication of intercellular crosstalk 418 between decidual cells and niche cells in mice. Int. J. Mol. 419 Sci. 22, 7696 420 26. Mareckova, M. et al. (2024) An integrated single-cell reference 421 atlas of the human endometrium. Nat. Genet. 56, 1925–1937 422 27. Pavlicev, M. et al. (2017) Single-cell transcriptomics of the 423 human placenta: inferring the cell communication network of 424 the maternal-fetal interface. Genome Res. 27, 349–361 425 28. Du, L. et al. (2021) Single-cell transcriptome analysis reveals 426 defective decidua stromal niche attributes to recurrent sponta- 427 neous abortion. Cell Prolif. 54, e13125 428 29. Queckborner, S. et al. (2021) Stromal heterogeneity in the 429 human proliferative endometrium-a single-cell RNA sequencing 430 study. J. Pers. Med. 11, 448 431 30. Hou, R. et al. (2023) Single-cell pro filing of the microenviron- 432 ment in decidual tissue from women with missed abortions. 433 Fertil. Steril. 119, 492–503 434 31. Kong, C.S. et al. (2021) Embryo biosensing by uterine natural 435 killer cells determines endometrial fate decisions at implanta- 436 tion. FASEB J. 35, e21336 437 32. Yang, Y. et al. (2021) Cell-cell communication at the embryo im- 438 plantation site of mouse uterus revealed by single-cell analysis. 439 Int. J. Mol. Sci. 22, 5177 440 33. Deng, B.P. et al. (2012) Soluble BAFF-R produced by decidual 441 stromal cells plays an inhibitory role in monocytes and macro- 442 phages. Reprod. Biomed. Online 24, 654–663 443 34. He, Y.Y. et al. (2007) Regulation of C-C motif chemokine ligand 444 2 and its receptor in human decidual stromal cells by 445 pregnancy-associated hormones in early gestation. Hum. 446 Reprod. 22, 2733–2742 447 35. Ruiz Magana, M.J. et al. (2020) Endometrial and decidual 448 stromal precursors show a different decidualization capacity. 449 Reproduction 160, 83–91 450 36. Shi, J.W. et al. (2021) WISP2/IGF1 promotes the survival of DSCs 451 and impairs the cytotoxicity of decidual NK cells. Reproduction 452 161, 425–436 453 37. Blanco, O. et al. (2008) Human decidual stromal cells express 454 HLA-G effects of cytokines and decidualization. Hum. Reprod. 455 23, 144–152 45638. Gellersen, B. and Brosens, J.J. (2014) Cyclic decidualization of 457the human endometrium in reproductive health and failure. 458Endocr. Rev. 35, 851–905 45939. Mor, G. et al. (2017) The unique immunological and microbial 460aspects of pregnancy. Nat. Rev. Immunol. 17, 469–482 46140. He, Y.Y. et al. (2012) The decidual stromal cells-secreted CCL2 462induces and maintains decidual leukocytes into Th2 bias in 463human early pregnancy. Clin. Immunol. 145, 161–173 46441. Hu, W.T. et al. (2015) Decidual stromal cell-derived IL-33 con- 465tributes to Th2 bias and inhibits decidual NK cell cytotoxicity 466through NF-kappaB signaling in human early pregnancy. 467J. Reprod. Immunol. 109, 52–65 46842. Suryawanshi, H. et al. (2018) A single-cell survey of the human 469first-trimester placenta and decidua. Sci. Adv. 4, eaau4788 47043. Qin, D. et al. (2024) CD24+ decidual stromal cells: a novel het- 471erogeneous population with impaired regulatory T cell induction 472and potential association with recurrent miscarriage. Fertil. 473Steril. 121, 519–530 47444. Garrido-Gomez, T. et al. (2017) Defective decidualization during 475and after severe preeclampsia reveals a possible maternal 476contribution to the etiology. Proc. Natl. Acad. Sci. U. S. A. 477114, E8468–E8477 47845. Ma, W. et al. (2022) MAX de ficiency impairs human endome- 479trial decidualization through down-regulating OSR2 in women 480with recurrent spontaneous abortion. Cell Tissue Res. 388, 481453–469 48246. Shih, A.J. et al. (2022) Single-cell analysis of menstrual endo- 483metrial tissues de fines phenotypes associated with endometri- 484osis. BMC Med. 20, 315 48547. Yang, J. et al. (2023) Single-cell RNA-seq reveals developmen- 486tal deficiencies in both the placentation and the decidualization 487i nw o m e nw i t hl a t e - o n s e tp r e e c l a m p s i a .Front. Immunol. 14, 4881142273 48948. Deryabin, P.I. and Borodkina, A.V. (2022) Stromal cell senes- 490cence contributes to impaired endometrial decidualization and 491defective interaction with trophoblast cells. Hum. Reprod. 37, 4921505–1524 49349. Brighton, P.J. et al. (2017) Clearance of senescent decidual cells 494by uterine natural killer cells in cycling human endometrium.eLife 4956, e31274 49650. Dominici, M. et al. (2006) Minimal criteria for defining multipotent 497mesenchymal stromal cells. The International Society for 498Cellular Therapy position statement. Cytotherapy 8, 315–317 49951. Gargett, C.E. et al. (2016) Endometrial stem/progenitor cells: 500the first 10 years. Hum. Reprod. Update 22, 137–163 50152. Ringden, O. et al. (2018) Placenta-derived decidua stromal cells 502for treatment of severe acute graft-versus-host disease. Stem 503Cells Transl. Med. 7, 325–331 50453. Zarnani, K. et al. (2024) In-utero transfer of decidualized 505endometrial stromal cells increases the frequency of regulatory 506T cells and normalizes the abortion rate in the CBA/J x DBA/2 507abortion model. Front. Immunol. 15, 1440388 50854. Aghajanova, L. et al. (2010) The bone marrow-derived human 509mesenchymal stem cell: potential progenitor of the endometrial 510stromal fibroblast. Biol. Reprod. 82, 1076–1087 51155. Taylor, H.S. (2004) Endometrial cells derived from donor stem 512cells in bone marrow transplant recipients. JAMA 292, 81–85 51356. Gil-Sanchis, C. et al. (2015) Contribution of different bone 514marrow-derived cell types in endometrial regeneration 515using an irradiated murine model. Fertil. Steril. 103, 5161596–1605.e1591 51757. Mamillapalli, R. et al. (2022) Characterization of bone marrow 518progenitor cell uterine engraftment and transdifferentiation. 519Reprod. Sci. 29, 2382–2390 52058. Diniz-da-Costa, M. et al. (2021) Characterization of highly prolif- 521erative decidual precursor cells during the window of implanta- 522tion in human endometrium. Stem Cells 39, 1067–1080 52359. Tal, R. et al. (2019) Adult bone marrow progenitors become 524decidual cells and contribute to embryo implantation and 525pregnancy. PLoS Biol. 17, e3000421 52660. Moridi, I. et al. (2017) Bone marrow stem cell chemotactic activ- 527ity is induced by elevated CXCl12 in endometriosis. Reprod. 528Sci. 24, 526–533 52961. Wang, X. et al. (2015) Chemoattraction of bone marrow-derived 530stem cells towards human endometrial stromal cells is mediated Trends in Immunology Trends in Immunology, Month 2025, Vol. xx, No. xx 13 UNCORRECTED PR OOF 531 by estradiol regulated CXCL12 and CXCR4 expression. Stem 532 Cell Res. 15, 14–22 533 62. Kin, K. et al. (2015) Cell-type phylogenetics and the origin of 534 endometrial stromal cells. Cell Rep. 10, 1398–1409 535 63. Crisan, M. et al. (2008) A perivascular origin for mesenchymal 536 stem cells in multiple human organs. Cell Stem Cell 3, 301–313 537 64. Davidson, S. et al. (2021) Fibroblasts as immune regulators in 538 infection, in flammation and cancer. Nat. Rev. Immunol. 21, 539 704–717 540 65. Buechler, M.B. and Turley, S.J. (2018) A short field guide to 541 fibroblast function in immunity. Semin. Immunol. 35, 48–58 542 66. Krishnamurty, A.T. and Turley, S.J. (2020) Lymph node stromal 543 cells: cartographers of the immune system. Nat. Immunol. 21, 544 369–380 545 6 7 .R o d d a ,L . B .et al. (2018) Single-cell RNA sequencing of 546 lymph node stromal cells reveals niche-associated heterogeneity. 547 Immunity 48, 1014–1028.e1016 548 68. Canete, J.D. et al. (2015) Ectopic lymphoid neogenesis is 549 strongly associated with activation of the IL-23 pathway in rheu- 550 matoid synovitis. Arthritis Res. Ther. 17, 173 551 69. Nayar, S. et al. (2019) Immuno fibroblasts are pivotal drivers of 552 tertiary lymphoid structure formation and local pathology. 553 Proc. Natl. Acad. Sci. U. S. A. 116, 13490–13497 554 70. Sylvestre, M. et al. (2023) KDM6B drives epigenetic reprogram- 555 ming associated with lymphoid stromal cell early commitment 556 and immune properties. Sci. Adv. 9, eadh2708Q11 557 71. Wang, Y. et al. (2013) IL-22 secreted by decidual stromal cells 558 and NK cells promotes the survival of human trophoblasts. 559 Int. J. Clin. Exp. Pathol. 6, 1781–1790 560 72. Logiodice, F. et al. (2019) Decidual interleukin-22-producing 561 CD4+ T cells (Th17/Th0/IL-22+ and Th17/Th2/IL-22+, Th2/ 562 IL-22+, Th0/IL-22+), which also produce IL-4, are involved 563 in the success of pregnancy. Int. J. Mol. Sci. 20, 428 564 73. Benezech, C. et al. (2010) Ontogeny of stromal organizer 565 cells during lymph node development. J. Immunol. 184, 566 4521–4530 567 74. Benezech, C. et al. (2012) Lymphotoxin-beta receptor signal- 568 ing through NF-kappaB2-RelB pathway reprograms adipo- 569 cyte precursors as lymph node stromal cells. Immunity 37, 570 721–734 571 75. Krautler, N.J. et al. (2012) Follicular dendritic cells emerge from 572 ubiquitous perivascular precursors. Cell 150, 194–206 573 76. Prados, A. et al. (2018) Characterization of mesenchymal stem/ 574 stromal cells with lymphoid tissue organizer cell potential in 575 tonsils from children. Eur. J. Immunol. 48, 829–843 576 77. Vacca, P. et al. (2015) Identification of diverse innate lymphoid 577 cells in human decidua. Mucosal Immunol. 8, 254–264 578 78. Munoz-Fernandez, R. et al. (2006) Follicular dendritic cells 579 are related to bone marrow stromal cell progenitors and to 580 myofibroblasts. J. Immunol. 177, 280–289 581 79. Carlino, C. et al. (2008) Recruitment of circulating NK cells 582 through decidual tissues: a possible mechanism controlling 583 NK cell accumulation in the uterus during early pregnancy. 584 Blood 111, 3108–3115 585 80. Keskin, D.B. et al. (2007) TGFbeta promotes conversion of 586 CD16+ peripheral blood NK cells into CD16- NK cells with sim- 587 ilarities to decidual NK cells. Proc. Natl. Acad. Sci. U. S. A. 104, 588 3378–3383 589 81. Siewiera, J. et al. (2015) Natural cytotoxicity receptor splice 590 variants orchestrate the distinct functions of human natural killer 591 cell subtypes. Nat. Commun. 6, 10183 592 82. Yang, H.L. et al. (2019) Decidual stromal cells promote the 593 differentiation of CD56(bright ) CD16(-) NK cells by secreting 594 IL-24 in early pregnancy. Am. J. Reprod. Immunol. 81, e13110 595 83. Vacca, P. et al. (2011) CD34+ hematopoietic precursors are 596 present in human decidua and differentiate into natural killer 597 cells upon interaction with stromal cells. Proc. Natl. Acad. Sci. 598 U. S. A. 108, 2402–2407 599 84. Lindau, R. et al. (2021) Decidual stromal cells support tolerance 600 at the human foetal-maternal interface by inducing regulatory 601 M2 macrophages and regulatory T-cells. J. Reprod. Immunol. 602 146, 103330 603 85. Croxatto, D. et al. (2014) Stromal cells from human decidua 604 exert a strong inhibitory effect on NK cell function and dendritic 605 cell differentiation. PLoS One 9, e89006 60686. Segerer, S.E. et al. (2012) MIC-1 (a multifunctional modulator of 607dendritic cell phenotype and function) is produced by decidual 608stromal cells and trophoblasts. Hum. Reprod. 27, 200–209 60987. Bachy, V. et al. (2008) Altered dendritic cell function in normal 610pregnancy. J. Reprod. Immunol. 78, 11–21 61188. Du, M.R. et al. (2014) Embryonic trophoblasts induce decidual 612regulatory T cell differentiation and maternal-fetal tolerance 613through thymic stromal lymphopoietin instructing dendritic 614cells. J. Immunol. 192, 1502–1511 61589. Erkers, T. et al. (2013) Decidual stromal cells promote 616regulatory T cells and suppress alloreactivity in a cell contact- 617dependent manner. Stem Cells Dev. 22, 2596–2605 61890. Buckley, C.D. et al. (2015) Stromal cells in chronic in flammation 619and tertiary lymphoid organ formation. Annu. Rev. Immunol. 33, 620715–745 62191. Zondervan, K.T. et al. (2020) Endometriosis. N. Engl. J. Med. 622382, 1244–1256 62392. Barragan, F. et al. (2016) Human endometrial fibroblasts 624derived from mesenchymal progenitors inherit progesterone 625resistance and acquire an in flammatory phenotype in the endo- 626metrial niche in endometriosis. Biol. Reprod. 94, 118 62793. Zutautas, K.B. et al. (2024) Tertiary lymphoid structures in 628endometriosis. F. S. Sci. 5, 335–341 62994. Rahmioglu, N. et al. (2023) The genetic basis of endometriosis 630and comorbidity with other pain and in flammatory conditions. 631Nat. Genet. 55, 423–436 63295. Symons, L.K. et al. (2020) Neutrophil recruitment and function 633in endometriosis patients and a syngeneic murine model. 634FASEB J. 34, 1558–1575 63596. Zhu, G. et al. (2018) Induction of tertiary lymphoid structures 636with antitumor function by a lymph node-derived stromal cell 637line. Front. Immunol. 9, 1609 63897. Martinez-Aguilar, R. et al. (2020) Menstrual blood-derived stro- 639mal cells modulate functional properties of mouse and human 640macrophages. Sci. Rep. 10, 21389 64198. Graham, J.J. et al. (2021) T helper cell immunity in pregnancy 642and influence on autoimmune disease progression.J. Autoimmun. 643121, 102651 64499. Piccinni, M.P. et al. (1998) Defective production of both 645leukemia inhibitory factor and type 2 T-helper cytokines by 646decidual T cells in unexplained recurrent abortions. Nat. Med. 6474, 1020–1024 648100. Wegmann, T.G. et al. (1993) Bidirectional cytokine interactions 649in the maternal-fetal relationship: is successful pregnancy a 650TH2 phenomenon? Immunol. Today 14, 353–356 651101. Medzhitov, R. (2021) The spectrum of in flammatory responses. 652Science 374, 1070–1075 653102. Bulmer, J.N. et al. (1991) Granulated lymphocytes in human 654endometrium: histochemical and immunohistochemical studies. 655Hum. Reprod. 6, 791–798 656103. King, A. et al. (1991) CD3- leukocytes present in the human 657uterus during early placentation: phenotypic and morphologic 658characterization of the CD56++ population. Dev. Immunol. 1, 659169–190 660104. Hanna, J. et al. (2006) Decidual NK cells regulate key develop- 661mental processes at the human fetal-maternal interface. Nat. 662Med. 12, 1065–1074 663105. Lash, G.E. et al. (2006) Expression of angiogenic growth factors 664by uterine natural killer cells during early pregnancy. J. Leukoc. 665Biol. 80, 572–580 666106. van der Zwan, A. et al. (2020) Visualizing dynamic changes at 667the maternal-fetal interface throughout human pregnancy by 668mass cytometry. Front. Immunol. 11, 571300 669107. Windsperger, K. et al. (2020) Densities of decidual high endo- 670thelial venules correlate with T-cell in flux in healthy pregnancies 671and idiopathic recurrent pregnancy losses. Hum. Reprod. 35, 6722467–2477 673108. Tirado-Gonzalez, I. et al. (2010) Reduced proportion of decidual 674DC-SIGN plus cells in human spontaneous abortion. Placenta 67531, 1019–1022 676109. Garcia-Flores, V. et al. (2023) A single-cell atlas of murine repro- 677ductive tissues during preterm labor. Cell Rep. 42, 111846 678110. Pique-Regi, R. et al. (2019) Single cell transcriptional signatures 679of the human placenta in term and preterm parturition. eLife 8, 680e52004 Trends in Immunology 14 Trends in Immunology, Month 2025, Vol. xx, No. xx UNCORRECTED PROOF 681 111. Fonseca, M.A.S. et al. (2023) Single-cell transcriptomic analysis 682 of endometriosis. Nat. Genet. 55, 255–267 683 112. Munoz-Fernandez, R. et al. (2014) Contractile activity of human 684 follicular dendritic cells. Immunol. Cell Biol. 92, 851–859 685 113. McCluggage, W.G. et al. (2001) CD10 is a sensitive and 686 diagnostically useful immunohistochemical marker of normal 687 endometrial stroma and of endometrial stromal neoplasms. 688 Histopathology 39, 273–278 689 114. Armulik, A. et al. (2011) Pericytes: developmental, physiological, 690 and pathological perspectives, problems, and promises. Dev. 691 Cell 21, 193–215 692 115. Heesters, B.A. et al. (2014) Follicular dendritic cells: dynamic 693 antigen libraries. Nat. Rev. Immunol. 14, 495–504 694 116. Lutge, M. et al. (2023) Conserved stromal-immune cell circuits 695 secure B cell homeostasis and function. Nat. Immunol. 24, 696 1149–1160 697 117. Link, A. et al. (2007) Fibroblastic reticular cells in lymph nodes 698 regulate the homeostasis of naive T cells. Nat. Immunol. 8, 699 1255–1265 700118. Pikor, N.B. et al. (2020) Remodeling of light and dark zone fol- 701licular dendritic cells governs germinal center responses. Nat. 702Immunol. 21, 649–659 703119. Robb, K.P. et al. (2024) Failure to launch commercially- 704approved mesenchymal stromal cell therapies: what's the 705path forward? Proceedings of the International Society for Cell 706& Gene Therapy (ISCT) Annual Meeting Roundtable held in 707May 2023, Palais des Congres de Paris, Organized by the 708ISCT MSC Scienti fic Committee. Cytotherapy 26, 413–417 709120. Sadeghi, B. et al. (2019) Long-term follow-up of a pilot study 710using placenta-derived decidua stromal cells for severe acute 711graft-versus-host disease. Biol. Blood Marrow Transplant. 25, 7121965–1969 713121. Sadeghi, B. et al. (2021) Conquering the cytokine storm in 714COVID-19-induced ARDS using placenta-derived decidua 715stromal cells. J. Cell. Mol. Med. 25, 10554–10564 716122. Bozorgmehr, M. et al. (2020) Endometrial and menstrual blood 717mesenchymal stem/stromal cells: biological properties and 718clinical application. Front. Cell Dev. Biol. 8, 497 719 Trends in Immunology Trends in Immunology, Month 2025, Vol. xx, No. xx 15