Pathophysiologic implications and therapeutic potentials of telocytes in multiorgan fibrosis.

Telocytes (TCs) represent a distinct population of interstitial cells ubiquitously distributed within the stromal compartment of numerous organs and characterized by unique morphologic, ultrastructural, and functional properties [ 1 – 6 ]. TCs are easily identifiable by their small piriform, spindle or triangular cell body and by their extremely thin, long, and branched telopodes, characteristic cytoplasmic processes with a typical moniliform aspect due to the alternation of very slim segments (podomers) and small enlarged portions (podoms) [ 1 – 6 ]. Within tissues, telopodes are usually organized in intricate 3D networks, which makes them highly specialized for both homocellular and heterocellular communications [ 1 – 6 ]. Moreover, telopodes can also establish contacts with the extracellular matrix (ECM) [ 7 ]. Under transmission electron microscopy (TEM), which is considered the gold standard technique to observe TCs, these stromal cells are characterized by a relatively small cell body containing scarce perinuclear cytoplasm, with mitochondria and endoplasmic reticulum cisternae mainly harbored within podoms [ 1 – 6 ]. In addition, telopodes are frequently surrounded by various types of extracellular vesicles, including exosomes, ectosomes, and multivesicular bodies, supporting a role for TCs in paracrine signaling and local cellular regulation [ 7 , 8 , 9 ▪▪ ]. In terms of immunophenotype, although TCs lack a distinctive antigenic profile, expression of CD34 alone or in combination with platelet-derived growth factor receptor α (PDGFRα) currently represents the most reliable label for their identification under light microscopy [ 1 – 6 ]. Nevertheless, the specific TC immunophenotype may vary across different tissue or organ systems, and heterogeneous TC subpopulations exhibiting distinct immunohistochemical features may coexist within the stroma of a single anatomical site [ 4 , 7 , 10 , 11 ]. Beyond these ultrastructural and immunophenotypic features, emerging data reveal that TCs also possess unique microRNA signatures and gene/protein expression profiles, which clearly distinguish them from classical fibroblasts and other stromal cell types [ 4 , 7 , 10 , 11 ]. While the full spectrum of TC functions remains to be fully elucidated, their characteristic spatial organization, extensive cell-to-cell communications, and paracrine activity via extracellular vesicle release suggest that these peculiar stromal cells may play significant roles in a wide range of physiological processes [ 2 , 4 , 7 , 10 , 11 ]. First, by forming 3D labyrinthine networks with their long and interconnecting telopodes, TCs may serve as a structural scaffold, guiding tissue morphogenesis, promoting postnatal repair, and maintaining tissue integrity [ 2 , 4 , 7 , 10 , 11 ]. Second, TCs have been proposed to mediate cellular signaling both via direct cell-to-cell contacts and indirectly through vesicle-mediated delivery of cytokines, growth factors, and RNAs (e.g., mRNAs, microRNAs and other noncoding RNAs) [ 2 , 4 , 7 , 10 , 11 ]. Third, TCs were also identified as an emerging component of stem cell niches of several organs, where they are thought to be crucial for stem cell survival, renewal, differentiation, maturation, and guidance [ 2 , 4 , 7 , 10 , 11 ]. Lastly, TCs are commonly regarded as active participants in immunomodulation/immunosurveillance, electrical signal conduction especially in the myometrium and myocardium, and regulation of intestinal motility, likely through the diffusion of the slow waves generated by the interstitial cells of Cajal within the enteric neuromuscular compartment [ 2 , 4 , 7 , 10 , 11 ]. Given their broad distribution and multifaceted functions, increasing interest has focused on the involvement of TCs in pathologic conditions, particularly fibrotic diseases, which are characterized by excessive ECM deposition and remain a challenging clinical problem due to their unclear pathogenesis and limited therapeutic options [ 4 , 6 , 7 , 10 – 14 ]. In this context, a growing body of evidence has recently established a strong association between TC morphologic and numerical impairment and the progression of a wide range of disorders featuring tissue fibrosis, including systemic sclerosis (SSc or scleroderma), ulcerative colitis (UC), Crohn's diseases (CD), liver fibrosis, myocardial fibrosis, and endometriosis among others (Fig. 1 ) [ 4 , 6 , 7 , 10 – 14 ]. Nonetheless, it should be considered that TC damage and loss may either be a consequence of the fibrotic process or precede the initial stages of fibrosis, and that a reciprocal causation between fibrosis establishment and TC impairment cannot be excluded (Fig. 1 ). However, since accumulating literature reported that TC transplantation and/or TC-derived secretome/extracellular vesicle administration were able to mitigate ECM deposition in preclinical models of several fibrotic diseases, TCs may be regarded as a promising innovative antifibrotic therapeutic tool [ 7 , 12 , 15 ▪ , 16 ▪ , 17 , 18 ]. Degeneration and reduction of telocytes, a distinctive stromal cell population possessing unique morphologic features and intercellular communication abilities, have been associated with the onset and progression of multiorgan fibrosis, including the skin, heart, lungs, gastrointestinal tract, kidneys, liver, organs of the reproductive systems, and cornea. Telocyte damage or loss may either be a consequence of the fibrotic process or precede the initial stages of fibrosis, and a reciprocal causation between fibrosis establishment and telocyte impairment may exist. In the present review, we will provide a comprehensive overview of the most important findings regarding TC involvement in different fibrotic conditions, and critically examine TC therapeutic potential for the management of these challenging pathologies. no caption available

By using an integrated immunohistochemical and TEM approach, CD34+/PDGFRα+ TCs have been identified throughout the full thickness of the corneal stroma, where they have been described to be aligned parallel to the corneal surface and interspersed among the ECM lamellae [ 69 ]. This regular spatial organization was hypothesized to contribute to the proper assembly and maintenance of the highly organized collagenous matrix, which is essential for ensuring corneal transparency and mechanical stability [ 69 ]. Notably, in the same study the authors also reported the existence of distinct TC subpopulations based on the co-expression of the stem cell marker c-kit/CD117, distinguishing between c-kit+ and c-kit– TC subpopulations [ 69 ]. Moreover, a comparative analysis between healthy corneas and corneas affected by keratoconus, a condition that leads to corneal fibrosis with disease progression, revealed a significant reduction in TC density within the pathologic tissues, particularly of the c-kit+ TC subset that likely represents a pool of progenitor cells with regenerative functions [ 69 ]. Of note, most of the remaining TCs in keratoconic corneas exhibited pronounced ultrastructural abnormalities, including organelle loss, cytoplasmic vacuolization, and telopode shrinkage or shortening, indicating not only a quantitative loss of these cells, but also a functional TC impairment during pathologic remodeling of corneal stroma [ 69 ].

Compelling evidence accumulated over the last decade has highlighted TCs as a distinct and functionally relevant stromal cell population with crucial roles in maintaining tissue architecture, mediating intercellular signaling, and supporting local stem cell niche renewal and regenerative properties [ 1 – 8 , 9 ▪▪ , 10 , 11 ]. Across a wide range of fibrotic disorders including SSc, IBD, liver and cardiac fibrosis, and fibrotic conditions affecting the reproductive, urinary, respiratory systems and the cornea, progressive loss or structural impairment of the TC network consistently emerged as a pathologic hallmark [ 4 , 6 , 7 , 10 – 14 ]. While the causative relationship between TC dysfunction and tissue fibrosis remains to be fully elucidated, current data suggest that TC depletion may represent either a trigger or a consequence of aberrant fibrotic cascades, primarily through the loss of homeostatic regulation over fibroblast activation, and ECM turnover [ 4 , 6 , 7 , 10 – 14 ]. Notably, in vitro and in vivo preclinical models have demonstrated that TC transplantation and/or administration of TC-derived secretome or exosomes can mitigate fibrogenesis, restore tissue architecture, and improve organ function, thereby underscoring their therapeutic potential (Fig. 3 ) [ 9 ▪▪ , 12 , 15 ▪ , 16 ▪ , 17 , 18 , 42 ▪▪ ]. Future research should aim to clarify the molecular mechanisms underlying TC-mediated antifibrotic effects, define their cell-to-cell and paracrine interactions with fibroblasts, immune cells and stem/progenitor cell niches, and explore novel strategies for their isolation, expansion, and delivery for therapeutic purposes. As tissue fibrosis remains a major unmet clinical challenge, TCs represent a new promising cellular target for the development of innovative antifibrotic therapies. Potential telocyte-based antifibrotic strategies. Several preclinical studies demonstrated that telocyte transplantation or administration of telocyte-derived secretome/extracellular vesicles can attenuate tissue fibrosis and restore normal tissue architecture, supporting their potential as novel antifibrotic therapeutic tools.

All the figures in this paper were created in part with BioRender.com. None. There are no conflicts of interest.