Abstract
The term ‘fibroblast’ often serves as a catch-all for a diverse array of mesenchymal cells, including perivascular cells, stromal progenitor cells and bona fide fibroblasts. Although phenotypically similar, these subpopulations are functionally distinct, maintaining tissue integrity and serving as local progenitor reservoirs. In response to tissue injury, these cells undergo a dynamic fibroblast–myofibroblast transition, marked by extracellular matrix secretion and contraction of actomyosin-based stress fibres. Importantly, whereas transient activation into myofibroblasts aids in tissue repair, persistent activation triggers pathological fibrosis. In this Review, we discuss the roles of mechanical cues, such as tissue stiffness and strain, alongside cell signalling pathways and extracellular matrix ligands in modulating myofibroblast activation and survival. We also highlight the role of epigenetic modifications and myofibroblast memory in physiological and pathological processes. Finally, we discuss potential strategies for therapeutically interfering with these factors and the associated signal transduction pathways to improve the outcome of dysregulated healing.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Virchow, R. A. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre (Hirschwald, 1858).
Schwann, T. Microscopical Researches into the Accordance in the Structure and Growth of Animals and Plants (English translation by Henry Smith, for the Sydenham Society, 1847) (Sydenham Society, 1839).
Liebert, H. Abhandlungen aus dem Gebiete der praktischen Chirurgie und der pathologischen Physiologie. Nach eigenen Untersuchungen und Erfahrungen und mit besonderer Rücksicht auf die Dieffenbach’sche Klinik in Berlin (Veit, 1849).
Ziegler, E. General Pathology; or, The Science of the Causes, Nature and Course of the Pathological Disturbances which Occur in the Living Subject (W. Wood and Company, 1899).
Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002).
Pakshir, P. et al. The myofibroblast at a glance. J. Cell Sci. 133, jcs227900 (2020).
Abercrombie, M., Flint, M. H. & James, D. W. Wound contraction in relation to collagen formation in scorbutic guinea pigs. J. Embryol. Exp. Morphol. 4, 167–175 (1956).
Gabbiani, G., Ryan, G. B. & Majno, G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 27, 549–550 (1971).
Majno, G., Gabbiani, G., Hirschel, B. J., Ryan, G. B. & Statkov, P. R. Contraction of granulation tissue in vitro: similarity to smooth muscle. Science 173, 548–550 (1971).
Schuster, R., Younesi, F., Ezzo, M. & Hinz, B. The role of myofibroblasts in physiological and pathological tissue repair. Cold Spring Harb. Perspect. Biol. 15, a041231 (2023).
Tallquist, M. D. & Molkentin, J. D. Redefining the identity of cardiac fibroblasts. Nat. Rev. Cardiol. 14, 484–491 (2017).
de Oliveira Camargo, R., Abual’anaz, B., Rattan, S. G., Filomeno, K. L. & Dixon, I. M. C. Novel factors that activate and deactivate cardiac fibroblasts: a new perspective for treatment of cardiac fibrosis. Wound Repair Regen. 29, 667–677 (2021).
Schreibing, F., Anslinger, T. M. & Kramann, R. Fibrosis in pathology of heart and kidney: from deep RNA-sequencing to novel molecular targets. Circ. Res. 132, 1013–1033 (2023).
Tacke, F., Puengel, T., Loomba, R. & Friedman, S. L. An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH. J. Hepatol. 79, 552–566 (2023).
Brugger, M. D. & Basler, K. The diverse nature of intestinal fibroblasts in development, homeostasis, and disease. Trends Cell Biol. 33, 834–849 (2023).
Wang, J. et al. Novel mechanisms and clinical trial endpoints in intestinal fibrosis. Immunol. Rev. 302, 211–227 (2021).
Adams, K. L. & Gallo, V. The diversity and disparity of the glial scar. Nat. Neurosci. 21, 9–15 (2018).
Moss, B. J., Ryter, S. W. & Rosas, I. O. Pathogenic mechanisms underlying idiopathic pulmonary fibrosis. Annu. Rev. Pathol. 17, 515–546 (2022).
Talbott, H. E., Mascharak, S., Griffin, M., Wan, D. C. & Longaker, M. T. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell 29, 1161–1180 (2022).
Layton, T. & Nanchahal, J. Recent advances in the understanding of Dupuytren’s disease. F1000Res 8, 231 (2019).
Wilson, S. E. Corneal myofibroblasts and fibrosis. Exp. Eye Res. 201, 108272 (2020).
Powell, S., Irnaten, M. & O’Brien, C. Glaucoma — ‘a stiff eye in a stiff body’. Curr. Eye Res. 48, 152–160 (2023).
Zeisberg, M. & Duffield, J. S. Resolved: EMT produces fibroblasts in the kidney. J. Am. Soc. Nephrol. 21, 1247–1253 (2010).
Rock, J. R. et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc. Natl Acad. Sci. USA 108, E1475–E1483 (2011).
Zhao, J. et al. Sox9 and Rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors. Nat. Commun. 12, 2564 (2021).
Sinha, M. et al. Direct conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue. Nat. Commun. 9, 936 (2018).
Bucala, R., Spiegel, L. A., Chesney, J., Hogan, M. & Cerami, A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol. Med. 1, 71–81 (1994).
Dias, D. O. et al. Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions. Nat. Commun. 12, 5501 (2021).
Soliman, H. et al. Multipotent stromal cells: one name, multiple identities. Cell Stem Cell 28, 1690–1707 (2021).
Wirka, R. C. et al. Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis. Nat. Med. 25, 1280–1289 (2019).
Shook, B. et al. The role of adipocytes in tissue regeneration and stem cell niches. Annu. Rev. Cell Dev. Biol. 6, 609–631 (2016).
Rognoni, E. et al. Fibroblast state switching orchestrates dermal maturation and wound healing. Mol. Syst. Biol. 14, e8174 (2018).
Jiang, D., Guo, R., Machens, H. G. & Rinkevich, Y. Diversity of fibroblasts and their roles in wound healing. Cold Spring Harb. Perspect. Biol. 15, a041222 (2023).
Papayannopoulou, T. G. & Martin, G. M. Alkaline phosphatase “constitutive” clones: evidence for de-novo heterogeneity of established human skin fibroblast strains. Exp. Cell Res. 45, 72–84 (1967).
Kisseleva, T. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl Acad. Sci. USA 109, 9448–9453 (2012).
Yao, L. et al. Temporal control of PDGFRα regulates the fibroblast-to-myofibroblast transition in wound healing. Cell Rep. 40, 111192 (2022).
Scott, R. W., Arostegui, M., Schweitzer, R., Rossi, F. M. V. & Underhill, T. M. Hic1 defines quiescent mesenchymal progenitor subpopulations with distinct functions and fates in skeletal muscle regeneration. Cell Stem Cell 25, 797–813.e9 (2019).
Abbasi, S. et al. Distinct regulatory programs control the latent regenerative potential of dermal fibroblasts during wound healing. Cell Stem Cell 27, 396–412.e6 (2020).
Hagood, J. S. et al. Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis. Am. J. Pathol. 167, 365–379 (2005).
Fendt, B. M. et al. Protein atlas of fibroblast specific protein 1 (FSP1)/S100A4. Histol. Histopathol. 38, 1391–1401 (2023).
Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).
Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013).
Di Carlo, S. E. & Peduto, L. The perivascular origin of pathological fibroblasts. J. Clin. Invest. 128, 54–63 (2018).
Younesi, F. S., Son, D. O., Firmino, J. & Hinz, B. Myofibroblast markers and microscopy detection methods in cell culture and histology. Methods Mol. Biol. 2299, 17–47 (2021).
Guimaraes-Camboa, N. et al. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20, 296–297 (2017).
Lemos, D. R. & Duffield, J. S. Tissue-resident mesenchymal stromal cells: implications for tissue-specific antifibrotic therapies. Sci. Transl. Med. 10, eaan5174 (2018).
Pittenger, M. F. et al. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen. Med. 4, 22 (2019).
El Agha, E. et al. Mesenchymal stem cells in fibrotic disease. Cell Stem Cell 21, 166–177 (2017).
Shaw, T. J. & Rognoni, E. Dissecting fibroblast heterogeneity in health and fibrotic disease. Curr. Rheumatol. Rep. 22, 33 (2020).
Muhl, L. et al. Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination. Nat. Commun. 11, 3953 (2020).
Soliman, H. et al. Pathogenic potential of Hic1-expressing cardiac stromal progenitors. Cell Stem Cell 26, 205–220.e8 (2020).
Kramann, R. et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16, 51–66 (2015).
Buechler, M. B. et al. Cross-tissue organization of the fibroblast lineage. Nature 593, 575–579 (2021).
Ascension, A. M., Fuertes-Alvarez, S., Ibanez-Sole, O., Izeta, A. & Arauzo-Bravo, M. J. Human dermal fibroblast subpopulations are conserved across single-cell RNA sequencing studies. J. Invest. Dermatol. 141, 1735–1744.e35 (2021).
Ushakumary, M. G., Riccetti, M. & Perl, A. T. Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration. Stem Cell Transl. Med. 10, 1021–1032 (2021).
Tsukui, T. et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat. Commun. 11, 1920 (2020).
Kadur Lakshminarasimha Murthy, P. et al. Human distal lung maps and lineage hierarchies reveal a bipotent progenitor. Nature 604, 111–119 (2022).
Konkimalla, A. et al. Transitional cell states sculpt tissue topology during lung regeneration. Cell Stem Cell 30, 1486–1502.e9 (2023).
Sikkema, L. et al. An integrated cell atlas of the lung in health and disease. Nat. Med. 29, 1563–1577 (2023).
Krishnamurty, A. T. et al. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature 611, 148–154 (2022).
Ligresti, G. et al. Mesenchymal cells in the lung: evolving concepts and their role in fibrosis. Gene 859, 147142 (2023).
Kuppe, C. et al. Spatial multi-omic map of human myocardial infarction. Nature 608, 766–777 (2022).
Filliol, A. et al. Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610, 356–365 (2022).
Davidson, S. et al. Fibroblasts as immune regulators in infection, inflammation and cancer. Nat. Rev. Immunol. 21, 704–717 (2021).
Rodda, L. B. et al. Single-cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity. Immunity 48, 1014–1028.e6 (2018).
Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).
Maglaviceanu, A., Wu, B. & Kapoor, M. Fibroblast-like synoviocytes: role in synovial fibrosis associated with osteoarthritis. Wound Repair Regen. 29, 642–649 (2021).
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
MacCarthy-Morrogh, L. & Martin, P. The hallmarks of cancer are also the hallmarks of wound healing. Sci. Signal. 13, eaay8690 (2020).
Tsukui, T. & Sheppard, D. Tracing the origin of pathologic pulmonary fibroblasts. Preprint at bioRxiv https://doi.org/10.1101/2022.11.18.517147 (2022).
Correa-Gallegos, D. et al. CD201+ fascia progenitors choreograph injury repair. Nature 623, 792–802 (2023).
Hinz, B., McCulloch, C. A. & Coelho, N. M. Mechanical regulation of myofibroblast phenoconversion and collagen contraction. Exp. Cell Res. 379, 119–128 (2019).
Hinz, B., Celetta, G., Tomasek, J. J., Gabbiani, G. & Chaponnier, C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell 12, 2730–2741 (2001).
Hinz, B., Mastrangelo, D., Iselin, C. E., Chaponnier, C. & Gabbiani, G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am. J. Pathol. 159, 1009–1020 (2001).
Hinz, B., Gabbiani, G. & Chaponnier, C. The NH2-terminal peptide of α-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J. Cell Biol. 157, 657–663 (2002).
Prunotto, M. et al. Stable incorporation of α-smooth muscle actin into stress fibers is dependent on specific tropomyosin isoforms. Cytoskeleton 72, 257–267 (2015).
Chen, A., Arora, P. D., McCulloch, C. A. & Wilde, A. Cytokinesis requires localized β-actin filament production by an actin isoform specific nucleator. Nat. Commun. 8, 1530 (2017).
Ronty, M. J. et al. Isoform-specific regulation of the actin-organizing protein palladin during TGF-β1-induced myofibroblast differentiation. J. Invest. Dermatol. 126, 2387–2396 (2006).
Alexander, J. I. et al. Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma. Sci. Rep. 11, 3802 (2021).
Jiang, D. et al. Two succeeding fibroblastic lineages drive dermal development and the transition from regeneration to scarring. Nat. Cell Biol. 20, 422–431 (2018).
Duong, T. E. et al. A single-cell regulatory map of postnatal lung alveologenesis in humans and mice. Cell Genom. 2, 100108 (2022).
Green, J., Endale, M., Auer, H. & Perl, A. K. Diversity of interstitial lung fibroblasts is regulated by platelet-derived growth factor receptor α kinase activity. Am. J. Respir. Cell Mol. Biol. 54, 532–545 (2016).
Desmouliere, A., Geinoz, A., Gabbiani, F. & Gabbiani, G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122, 103–111 (1993).
Serini, G. & Gabbiani, G. Modulation of α-smooth muscle actin expression in fibroblasts by transforming growth factor-β isoforms: an in vivo and in vitro study. Wound Rep. Reg. 4, 278–287 (1996).
Lodyga, M. & Hinz, B. TGF-β1 — a truly transforming growth factor in fibrosis and immunity. Semin. Cell Dev. Biol. 101, 123–139 (2020).
Massague, J. & Sheppard, D. TGF-β signaling in health and disease. Cell 186, 4007–4037 (2023).
Frangogiannis, N. G. Transforming growth factor-β in myocardial disease. Nat. Rev. Cardiol. 19, 435–455 (2022).
Bialik, J. F. et al. Profibrotic epithelial phenotype: a central role for MRTF and TAZ. Sci. Rep. 9, 4323 (2019).
Luo, K. Signaling cross talk between TGF-β/Smad and other signaling pathways. Cold Spring Harb. Perspect. Biol. 9, a022137 (2017).
Zhang, Y. E. Non-smad signaling pathways of the TGF-β family. Cold Spring Harb. Perspect. Biol. 19, 128–139 (2017).
Derynck, R. & Budi, E. H. Specificity, versatility, and control of TGF-β family signaling. Sci. Signal. 12, eaav5183 (2019).
Bhattacharyya, S. et al. Pharmacological inhibition of Toll-like receptor-4 signaling by TAK242 prevents and induces regression of experimental organ fibrosis. Front. Immunol. 9, 2434 (2018).
Ng, B., Cook, S. A. & Schafer, S. Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway. Exp. Mol. Med. 52, 1871–1878 (2020).
Schuppan, D., Ashfaq-Khan, M., Yang, A. T. & Kim, Y. O. Liver fibrosis: direct antifibrotic agents and targeted therapies. Matrix Biol. 68-69, 435–451 (2018).
Sato, S., Yanagihara, T. & Kolb, M. R. J. Therapeutic targets and early stage clinical trials for pulmonary fibrosis. Expert Opin. Investig. Drugs 28, 19–28 (2019).
Lagares, D. & Hinz, B. Animal and human models of tissue repair and fibrosis: an introduction. Methods Mol. Biol. 2299, 277–290 (2021).
Tschumperlin, D. J., Ligresti, G., Hilscher, M. B. & Shah, V. H. Mechanosensing and fibrosis. J. Clin. Invest. 128, 74–84 (2018).
Sawant, M. et al. A story of fibers and stress: matrix-embedded signals for fibroblast activation in the skin. Wound Repair Regen. 29, 515–530 (2021).
Janmey, P. A., Georges, P. C. & Hvidt, S. Basic rheology for biologists. Methods Cell Biol. 83, 3–27 (2007).
Dooling, L. J., Saini, K., Anlas, A. A. & Discher, D. E. Tissue mechanics coevolves with fibrillar matrisomes in healthy and fibrotic tissues. Matrix Biol. 111, 153–188 (2022).
Kuehlmann, B., Bonham, C. A., Zucal, I., Prantl, L. & Gurtner, G. C. Mechanotransduction in wound healing and fibrosis. J. Clin. Med. 9, 1423 (2020).
Brown, R. A., Prajapati, R., McGrouther, D. A., Yannas, I. V. & Eastwood, M. Tensional homeostasis in dermal fibroblasts: mechanical responses to mechanical loading in three-dimensional substrates. J. Cell Physiol. 175, 323–332 (1998).
Pehrsson, M. et al. An MMP-degraded and cross-linked fragment of type III collagen as a non-invasive biomarker of hepatic fibrosis resolution. Liver Int. 42, 1605–1617 (2022).
Ravassa, S. et al. Prediction of left ventricular reverse remodeling and outcomes by circulating collagen-derived peptides. JACC Heart Fail. 11, 58–72 (2023).
Hansen, A. H. et al. A serologically assessed neo-epitope biomarker of cellular fibronectin degradation is related to pulmonary fibrosis. Clin. Biochem. 118, 110599 (2023).
Leeming, D. J. et al. A serological marker of the N-terminal neoepitope generated during LOXL2 maturation is elevated in patients with cancer or idiopathic pulmonary fibrosis. Biochem. Biophys. Rep. 17, 38–43 (2019).
Litvinov, R. I. & Weisel, J. W. Fibrin mechanical properties and their structural origins. Matrix Biol. 60-61, 110–123 (2017).
Barker, T. H. & Engler, A. J. The provisional matrix: setting the stage for tissue repair outcomes. Matrix Biol. 60-61, 1–4 (2017).
Lin, J., Sorrells, M. G., Lam, W. A. & Neeves, K. B. Physical forces regulating hemostasis and thrombosis: vessels, cells, and molecules in illustrated review. Res. Pract. Thromb. Haemost. 5, e12548 (2021).
Georges, P. C. et al. Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G1147–G1154 (2007).
Selcuk, K. et al. Tissue transglutaminase 2 has higher affinity for relaxed than for stretched fibronectin fibers. Matrix Biol. 125, 113–132 (2023).
Achterberg, V. F. et al. The nano-scale mechanical properties of the extracellular matrix regulate dermal fibroblast function. J. Invest. Dermatol. 134, 1862–1872 (2014).
Fell, S., Wang, Z., Blanchard, A., Nanthakumar, C. & Griffin, M. Transglutaminase 2: a novel therapeutic target for idiopathic pulmonary fibrosis using selective small molecule inhibitors. Amino Acids 53, 205–217 (2021).
Piersma, B. & Bank, R. A. Collagen cross-linking mediated by lysyl hydroxylase 2: an enzymatic battlefield to combat fibrosis. Essays Biochem. 63, 377–387 (2019).
Vallet, S. D. & Ricard-Blum, S. Lysyl oxidases: from enzyme activity to extracellular matrix cross-links. Essays Biochem. 63, 349–364 (2019).
Barry-Hamilton, V. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16, 1009–1017 (2010).
Bhole, A. P. et al. Mechanical strain enhances survivability of collagen micronetworks in the presence of collagenase: implications for load-bearing matrix growth and stability. Philos. Trans. A Math. Phys. Eng. Sci. 367, 3339–3362 (2009).
Saini, K., Cho, S., Dooling, L. J. & Discher, D. E. Tension in fibrils suppresses their enzymatic degradation — a molecular mechanism for ‘use it or lose it’. Matrix Biol. 85-86, 34–46 (2020).
Schuster, R., Rockel, J. S., Kapoor, M. & Hinz, B. The inflammatory speech of fibroblasts. Immunol. Rev. 302, 126–146 (2021).
Saraswathibhatla, A., Indana, D. & Chaudhuri, O. Cell-extracellular matrix mechanotransduction in 3D. Nat. Rev. Mol. Cell Biol. 24, 495–416 (2023).
Kanchanawong, P. & Calderwood, D. A. Organization, dynamics and mechanoregulation of integrin-mediated cell–ECM adhesions. Nat. Rev. Mol. Cell Biol. 24, 142–161 (2023).
Govindaraju, P., Todd, L., Shetye, S., Monslow, J. & Pure, E. CD44-dependent inflammation, fibrogenesis, and collagenolysis regulates extracellular matrix remodeling and tensile strength during cutaneous wound healing. Matrix Biol. 75-76, 314–330 (2019).
Razinia, Z. et al. Stiffness-dependent motility and proliferation uncoupled by deletion of CD44. Sci. Rep. 7, 16499 (2017).
Coelho, N. M. et al. Discoidin domain receptor 1 mediates myosin-dependent collagen contraction. Cell Rep. 18, 1774–1790 (2017).
Guerrot, D. et al. Discoidin domain receptor 1 is a major mediator of inflammation and fibrosis in obstructive nephropathy. Am. J. Pathol. 179, 83–91 (2011).
Moll, S. et al. DDR1 role in fibrosis and its pharmacological targeting. Biochim. Biophys. Acta Mol. Cell Res. 1866, 118474 (2019).
Li, R. & Frangogiannis, N. G. Integrins in cardiac fibrosis. J. Mol. Cell Cardiol. 172, 1–13 (2022).
Levine, D. et al. Expression of the integrin α8β1 during pulmonary and hepatic fibrosis. Am. J. Pathol. 156, 1927–1935 (2000).
Primac, I. et al. Stromal integrin α11 regulates PDGFR-β signaling and promotes breast cancer progression. J. Clin. Invest. 129, 4609–4628 (2019).
Yokosaki, Y. & Nishimichi, N. New therapeutic targets for hepatic fibrosis in the integrin family, α8β1 and α11β1, induced specifically on activated stellate cells. Int. J. Mol. Sci. 22, 12794 (2021).
Schulz, J. N. et al. Reduced granulation tissue and wound strength in the absence of α11β1 integrin. J. Invest. Dermatol. 135, 1435–1444 (2015).
Frangogiannis, N. G. The extracellular matrix in myocardial injury, repair, and remodeling. J. Clin. Invest. 127, 1600–1612 (2017).
Klingberg, F., Hinz, B. & White, E. S. The myofibroblast matrix: implications for tissue repair and fibrosis. J. Pathol. 229, 298–309 (2013).
Fiore, V. F. et al. αvβ3 integrin drives fibroblast contraction and strain stiffening of soft provisional matrix during progressive fibrosis. JCI Insight 3, e97597 (2018).
Goffin, J. M. et al. Focal adhesion size controls tension-dependent recruitment of α-smooth muscle actin to stress fibers. J. Cell Biol. 172, 259–268 (2006).
Hu, P. et al. SEMA7a primes integrin α5β1 engagement instructing fibroblast mechanotransduction, phenotype and transcriptional programming. Matrix Biol. 121, 179–193 (2023).
Reed, N. I. et al. The αvβ1 integrin plays a critical in vivo role in tissue fibrosis. Sci. Transl. Med. 7, 288ra279 (2015).
Munger, J. S. et al. A mechanism for regulating pulmonary inflammation and fibrosis: the integrin αvβ6 binds and activates latent TGF β1. Cell 96, 319–328 (1999).
Edwards, J. P., Thornton, A. M. & Shevach, E. M. Release of active TGF-β1 from the latent TGF-β1/GARP complex on T regulatory cells is mediated by integrin β8. J. Immunol. 193, 2843–2849 (2014).
Prager-Khoutorsky, M. et al. Fibroblast polarization is a matrix-rigidity-dependent process controlled by focal adhesion mechanosensing. Nat. Cell Biol. 13, 1457–U1178 (2011).
Noskovicova, N., Hinz, B. & Pakshir, P. Implant fibrosis and the underappreciated role of myofibroblasts in the foreign body reaction. Cells 10, 1794 (2021).
Dugina, V., Fontao, L., Chaponnier, C., Vasiliev, J. & Gabbiani, G. Focal adhesion features during myofibroblastic differentiation are controlled by intracellular and extracellular factors. J. Cell Sci. 114, 3285–3296 (2001).
Singer, I. I., Kawka, D. W., Kazazis, D. M. & Clark, R. A. In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface. J. Cell Biol. 98, 2091–2106 (1984).
Goult, B. T., Yan, J. & Schwartz, M. A. Talin as a mechanosensitive signaling hub. J. Cell Biol. 217, 3776–3784 (2018).
Sun, Z., Costell, M. & Fassler, R. Integrin activation by talin, kindlin and mechanical forces. Nat. Cell Biol. 21, 25–31 (2019).
Godbout, E. et al. Kindlin-2 mediates mechanical activation of cardiac myofibroblasts. Cells 9, 2702 (2020).
Zhang, P. et al. Kindlin-2 acts as a key mediator of lung fibroblast activation and pulmonary fibrosis progression. Am. J. Respir. Cell Mol. Biol. 65, 54–69 (2021).
Yamamura, Y. et al. Myocardin-related transcription factor contributes to renal fibrosis through the regulation of extracellular microenvironment surrounding fibroblasts. FASEB J. 37, e23005 (2023).
Nuchel, J. et al. TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators. Autophagy 14, 465–486 (2018).
Thannickal, V. J. et al. Myofibroblast differentiation by transforming growth factor-β1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J. Biol. Chem. 278, 12384–12389 (2003).
Chen, K. et al. Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting. Sci. Transl. Med. 14, eabj9152 (2022).
Wipff, P. J., Rifkin, D. B., Meister, J. J. & Hinz, B. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).
Henderson, N. C. et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19, 1617–1624 (2013).
Shi, M. et al. Latent TGF-β structure and activation. Nature 474, 343–349 (2011).
Rifkin, D. B., Rifkin, W. J. & Zilberberg, L. LTBPs in biology and medicine: LTBP diseases. Matrix Biol. 71-72, 90–99 (2018).
Qin, Y. et al. A milieu molecule for TGF-β required for microglia function in the nervous system. Cell 174, 156–171 (2018).
Lienart, S. et al. Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells. Science 362, 952–956 (2018).
Murphy-Ullrich, J. E. & Suto, M. J. Thrombospondin-1 regulation of latent TGF-β activation: a therapeutic target for fibrotic disease. Matrix Biol. 68-69, 28–43 (2018).
Noskovicova, N. et al. Suppression of the fibrotic encapsulation of silicone implants by inhibiting the mechanical activation of pro-fibrotic TGF-β. Nat. Biomed. Eng. 5, 1437–1456 (2021).
Liu, S. et al. Expression of integrin β1 by fibroblasts is required for tissue repair in vivo. J. Cell Sci. 123, 3674–3682 (2010).
Le, V. Q. et al. A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8. Proc. Natl Acad. Sci. USA 120, e2304874120 (2023).
Goodwin, A. T. et al. Stretch regulates alveologenesis and homeostasis via mesenchymal Gαq/11-mediated TGFβ2 activation. Development 150, dev201046 (2023).
Klingberg, F. et al. Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation. J. Cell Biol. 207, 283–297 (2014).
Zollinger, A. J. & Smith, M. L. Fibronectin, the extracellular glue. Matrix Biol. 60-61, 27–37 (2017).
Dinesh, N. E. H., Campeau, P. M. & Reinhardt, D. P. Fibronectin isoforms in skeletal development and associated disorders. Am. J. Physiol. Cell Physiol. 323, C536–C549 (2022).
Serini, G. et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-β1. J. Cell Biol. 142, 873–881 (1998).
Klingberg, F. et al. The fibronectin ED-A domain enhances recruitment of latent TGF-β-binding protein-1 to the fibroblast matrix. J. Cell Sci. 131, jcs201293 (2018).
Vogel, V. Unraveling the mechanobiology of extracellular matrix. Annu. Rev. Physiol. 80, 353–387 (2018).
Zhong, C. et al. Rho-mediated contractility exposes a cryptic site in fibronectin and induces fibronectin matrix assembly. J. Cell Biol. 141, 539–551 (1998).
Gao, M. et al. Structure and functional significance of mechanically unfolded fibronectin type III1 intermediates. Proc. Natl Acad. Sci. USA 100, 14784–14789 (2003).
Oberhauser, A. F., Badilla-Fernandez, C., Carrion-Vazquez, M. & Fernandez, J. M. The mechanical hierarchies of fibronectin observed with single-molecule AFM. J. Mol. Biol. 319, 433–447 (2002).
Adapala, R. K. et al. TRPV4 mechanotransduction in fibrosis. Cells 10, 3053 (2021).
Stewart, L. & Turner, N. A. Channelling the force to reprogram the matrix: mechanosensitive ion channels in cardiac fibroblasts. Cells 10, 990 (2021).
Wang, A. Y. et al. DDR1 associates with TRPV4 in cell-matrix adhesions to enable calcium-regulated myosin activity and collagen compaction. J. Cell Physiol. 237, 2451–2468 (2022).
Matthews, B. D. et al. Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface β1 integrins. Integr. Biol. 2, 435–442 (2010).
Grove, L. M. et al. Translocation of TRPV4-PI3Kγ complexes to the plasma membrane drives myofibroblast transdifferentiation. Sci. Signal. 12, eaau1533 (2019).
Zou, Y. et al. Activation of transient receptor potential vanilloid 4 is involved in pressure overload-induced cardiac hypertrophy. eLife 11, e74519 (2022).
Sharma, S. et al. TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation. Am. J. Physiol. Cell Physiol. 312, C562–C572 (2017).
Um, J. Y. et al. Transient receptor potential vanilloid-3 (TRPV3) channel induces dermal fibrosis via the TRPV3/TSLP/Smad2/3 pathways in dermal fibroblasts. J. Dermatol. Sci. 97, 117–124 (2020).
Coste, B. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55–60 (2010).
He, J. et al. Mechanical stretch promotes hypertrophic scar formation through mechanically activated cation channel Piezo1. Cell Death Dis. 12, 226 (2021).
Fu, Y. et al. Targeting mechanosensitive piezo1 alleviated renal fibrosis through p38MAPK-YAP pathway. Front. Cell Dev. Biol. 9, 741060 (2021).
Emig, R. et al. Piezo1 channels contribute to the regulation of human atrial fibroblast mechanical properties and matrix stiffness sensing. Cells 10, 663 (2021).
Yao, M. et al. Force- and cell state-dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry. Sci. Adv. 8, eabo1461 (2022).
Follonier, L., Schaub, S., Meister, J. J. & Hinz, B. Myofibroblast communication is controlled by intercellular mechanical coupling. J. Cell Sci. 121, 3305–3316 (2008).
Ellefsen, K. L. et al. Myosin-II mediated traction forces evoke localized Piezo1-dependent Ca2+ flickers. Commun. Biol. 2, 298 (2019).
Follonier Castella, L., Buscemi, L., Godbout, C., Meister, J. J. & Hinz, B. A new lock-step mechanism of matrix remodelling based on subcellular contractile events. J. Cell Sci. 123, 1751–1760 (2010).
Parizi, M., Howard, E. W. & Tomasek, J. J. Regulation of LPA-promoted myofibroblast contraction: role of Rho, myosin light chain kinase, and myosin light chain phosphatase. Exp. Cell Res. 254, 210–220 (2000).
Burridge, K. & Guilluy, C. Focal adhesions, stress fibers and mechanical tension. Exp. Cell Res. 343, 14–20 (2016).
Kim, T. J. et al. Substrate rigidity regulates Ca2+ oscillation via RhoA pathway in stem cells. J. Cell Physiol. 218, 285–293 (2009).
Godbout, C. et al. The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts. PLoS One 8, e64560 (2013).
Nomikou, E., Livitsanou, M., Stournaras, C. & Kardassis, D. Transcriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: implications for the pathogenesis of human diseases. Cell Mol. Life Sci. 75, 2111–2124 (2018).
Htwe, S. S. et al. Role of Rho-associated coiled-coil forming kinase isoforms in regulation of stiffness-induced myofibroblast differentiation in lung fibrosis. Am. J. Respir. Cell Mol. Biol. 56, 772–783 (2017).
Liu, Q. et al. Belumosudil, ROCK2-specific inhibitor, alleviates cardiac fibrosis by inhibiting cardiac fibroblasts activation. Am. J. Physiol. Heart Circ. Physiol. 323, H235–H247 (2022).
Knipe, R. S. et al. The Rho kinase isoforms ROCK1 and ROCK2 each contribute to the development of experimental pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 58, 471–481 (2018).
Sakai, N. et al. Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor. Kidney Int. 91, 628–641 (2017).
Ungefroren, H. et al. Signaling crosstalk of TGF-β/ALK5 and PAR2/PAR1: a complex regulatory network controlling fibrosis and cancer. Int. J. Mol. Sci. 19, 1568 (2018).
Zhang, H., Ren, L. & Shivnaraine, R. V. Targeting GPCRs to treat cardiac fibrosis. Front. Cardiovasc. Med. 9, 1011176 (2022).
Haak, A. J. et al. Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis. Sci. Transl. Med. 11, eaau6296 (2019).
Dooling, L. J. & Discher, D. E. Inhibiting tumor fibrosis and actomyosin through GPCR activation. Trends Cancer 5, 197–199 (2019).
Oh, R. S. et al. RNAi screening identifies a mechanosensitive ROCK-JAK2-STAT3 network central to myofibroblast activation. J. Cell Sci. 131, jcs209932 (2018).
Eguchi, A. et al. GRK5 is a regulator of fibroblast activation and cardiac fibrosis. Proc. Natl Acad. Sci. USA 118, e2012854118 (2021).
Dey, A., Varelas, X. & Guan, K. L. Targeting the hippo pathway in cancer, fibrosis, wound healing and regenerative medicine. Nat. Rev. Drug Discov. 19, 480–494 (2020).
Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).
Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171, 1397–1410.e14 (2017).
Kofler, M. et al. Mediated nuclear import and export of TAZ and the underlying molecular requirements. Nat. Commun. 9, 4966 (2018).
He, X. et al. Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis. JCI Insight 7, e146243 (2022).
Szeto, S. G. et al. YAP/TAZ are mechanoregulators of TGF-β-smad signaling and renal fibrogenesis. J. Am. Soc. Nephrol. 27, 3117–3128 (2016).
Link, P. A. et al. Combined control of the fibroblast contractile program by YAP and TAZ. Am. J. Physiol. Lung Cell Mol. Physiol. 322, L23–L32 (2022).
Reggiani, F. et al. Not identical twins. Trends Biochem. Sci. 46, 154–168 (2021).
Miranda, M. Z., Lichner, Z., Szaszi, K. & Kapus, A. MRTF: basic biology and role in kidney disease. Int. J. Mol. Sci. 22, 6040 (2021).
Masszi, A. et al. Fate-determining mechanisms in epithelial-myofibroblast transition: major inhibitory role for Smad3. J. Cell Biol. 188, 383–399 (2010).
Ezzo, M. & Hinz, B. Novel approaches to target fibroblast mechanotransduction in fibroproliferative diseases. Pharmacol. Ther. 250, 108528 (2023).
Velasquez, L. S. et al. Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing. Proc. Natl Acad. Sci. USA 110, 16850–16855 (2013).
Leal, A. S., Misek, S. A., Lisabeth, E. M., Neubig, R. R. & Liby, K. T. The Rho/MRTF pathway inhibitor CCG-222740 reduces stellate cell activation and modulates immune cell populations in KrasG12D; Pdx1-Cre (KC) mice. Sci. Rep. 9, 7072 (2019).
Johnson, L. A. et al. Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-β-induced fibrogenesis in human colonic myofibroblasts. Inflamm. Bowel Dis. 20, 154–165 (2014).
Yu-Wai-Man, C. et al. Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis. Sci. Rep. 7, 518 (2017).
Basta, M. D. et al. Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis. iScience 26, 106570 (2023).
Hinz, B. & Lagares, D. Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nat. Rev. Rheumatol. 16, 11–31 (2020).
Merkt, W., Zhou, Y., Han, H. & Lagares, D. Myofibroblast fate plasticity in tissue repair and fibrosis: deactivation, apoptosis, senescence and reprogramming. Wound Repair Regen. 29, 678–691 (2021).
Desmoulière, A., Redard, M., Darby, I. & Gabbiani, G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am. J. Pathol. 146, 56–66 (1995).
Soppert, J. et al. Soluble CD74 reroutes MIF/CXCR4/AKT-mediated survival of cardiac myofibroblasts to necroptosis. J. Am. Heart Assoc. 7, e009384 (2018).
Takemura, G. et al. Role of apoptosis in the disappearance of infiltrated and proliferated interstitial cells after myocardial infarction. Circ. Res. 82, 1130–1138 (1998).
Tschumperlin, D. J. & Lagares, D. Mechano-therapeutics: targeting mechanical signaling in fibrosis and tumor stroma. Pharmacol. Ther. 212, 107575 (2020).
O’Reilly, S. Epigenetics in fibrosis. Mol. Asp. Med. 54, 89–102 (2017).
Moran-Salvador, E. & Mann, J. Epigenetics and liver fibrosis. Cell Mol. Gastroenterol. Hepatol. 4, 125–134 (2017).
Balestrini, J. L., Chaudhry, S., Sarrazy, V., Koehler, A. & Hinz, B. The mechanical memory of lung myofibroblasts. Integr. Biol. 4, 410–421 (2012).
Li, C. X. et al. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mater. 16, 379–389 (2017).
Yang, C., Tibbitt, M. W., Basta, L. & Anseth, K. S. Mechanical memory and dosing influence stem cell fate. Nat. Mater. 13, 645–652 (2014).
Lee, J., Abdeen, A. A. & Kilian, K. A. Rewiring mesenchymal stem cell lineage specification by switching the biophysical microenvironment. Sci. Rep. 4, 5188 (2014).
Talele, N. P., Fradette, J., Davies, J. E., Kapus, A. & Hinz, B. Expression of α-smooth muscle actin determines the fate of mesenchymal stromal cells. Stem Cell Rep. 4, 1016–1030 (2015).
Scott, A. K. et al. Mechanical memory stored through epigenetic remodeling reduces cell therapeutic potential. Biophys. J. 122, 1428–1444 (2023).
Roy, B. et al. Fibroblast rejuvenation by mechanical reprogramming and redifferentiation. Proc. Natl Acad. Sci. USA 117, 10131–10141 (2020).
Price, C. C., Mathur, J., Boerckel, J. D., Pathak, A. & Shenoy, V. B. Dynamic self-reinforcement of gene expression determines acquisition of cellular mechanical memory. Biophys. J. 120, 5074–5089 (2021).
Heo, S. J. et al. Biophysical regulation of chromatin architecture instills a mechanical memory in mesenchymal stem cells. Sci. Rep. 5, 16895 (2015).
Ligresti, G. et al. CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis. JCI Insight 4, e127111 (2019).
Killaars, A. R. et al. Extended exposure to stiff microenvironments leads to persistent chromatin remodeling in human mesenchymal stem cells. Adv. Sci. 6, 1801483 (2019).
Killaars, A. R., Walker, C. J. & Anseth, K. S. Nuclear mechanosensing controls MSC osteogenic potential through HDAC epigenetic remodeling. Proc. Natl Acad. Sci. USA 117, 21258–21266 (2020).
Walker, C. J. et al. Nuclear mechanosensing drives chromatin remodelling in persistently activated fibroblasts. Nat. Biomed. Eng. 5, 1485–1499 (2021).
Walker, C. J. et al. Extracellular matrix stiffness controls cardiac valve myofibroblast activation through epigenetic remodeling. Bioeng. Transl. Med. 7, e10394 (2022).
Swift, J. et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341, 1240104 (2013).
Miroshnikova, Y. A. & Wickstrom, S. A. Mechanical forces in nuclear organization. Cold Spring Harb. Perspect. Biol. 14, a039685 (2022).
Janota, C. S., Calero-Cuenca, F. J. & Gomes, E. R. The role of the cell nucleus in mechanotransduction. Curr. Opin. Cell Biol. 63, 204–211 (2020).
Kalukula, Y., Stephens, A. D., Lammerding, J. & Gabriele, S. Mechanics and functional consequences of nuclear deformations. Nat. Rev. Mol. Cell Biol. 23, 583–602 (2022).
Dupont, S. & Wickstrom, S. A. Mechanical regulation of chromatin and transcription. Nat. Rev. Genet. 23, 624–643 (2022).
Maniotis, A. J., Chen, C. S. & Ingber, D. E. Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. Proc. Natl Acad. Sci. USA 94, 849–854 (1997).
Xia, Y. et al. Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle. J. Cell Biol. 218, 2545–2563 (2019).
Nava, M. M. et al. Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell 181, 800–817.e22 (2020).
Tajik, A. et al. Transcription upregulation via force-induced direct stretching of chromatin. Nat. Mater. 15, 1287–1296 (2016).
Rai, R. et al. A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis. Epigenetics 12, 1004–1013 (2017).
Nural-Guvener, H. F. et al. HDAC class I inhibitor, Mocetinostat, reverses cardiac fibrosis in heart failure and diminishes CD90+ cardiac myofibroblast activation. Fibrogenesis Tissue Repair 7, 10 (2014).
Ghosh, A. K. et al. p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-β: epigenetic feed-forward amplification of fibrosis. J. Investig. Dermatol. 133, 1302–1310 (2013).
Williams, L. M. et al. Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300. Proc. Natl Acad. Sci. USA 117, 20753–20763 (2020).
Saito, S. et al. HDAC8 inhibition ameliorates pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 316, L175–L186 (2019).
Jones, D. L. et al. TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression. J. Cell Sci. 132, jcs233486 (2019).
Guo, W., Shan, B., Klingsberg, R. C., Qin, X. & Lasky, J. A. Abrogation of TGF-β1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition. Am. J. Physiol. Lung Cell Mol. Physiol. 297, L864–L870 (2009).
Pang, M. et al. Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy. Am. J. Physiol. Renal Physiol. 297, F996–F1005 (2009).
Dou, C. et al. P300 acetyltransferase mediates stiffness-induced activation of hepatic stellate cells into tumor-promoting myofibroblasts. Gastroenterology 154, 2209–2221.e14 (2018).
Krämer, M. et al. Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Ann. Rheum. Dis. 72, 614–620 (2013).
Perugorria, M. J. et al. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology 56, 1129–1139 (2012).
Tian, W. et al. Myocardin-related transcription factor A (MRTF-A) plays an essential role in hepatic stellate cell activation by epigenetically modulating TGF-β signaling. Int. J. Biochem. Cell Biol. 71, 35–43 (2016).
Page, A. et al. Alcohol directly stimulates epigenetic modifications in hepatic stellate cells. J. Hepatol. 62, 388–397 (2015).
Mann, J. et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138, 705–714 (2010).
Jiang, Y. et al. Histone H3K9 demethylase JMJD1A modulates hepatic stellate cells activation and liver fibrosis by epigenetically regulating peroxisome proliferator‐activated receptor γ. FASEB J. 29, 1830–1841 (2015).
Irifuku, T. et al. Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression. Kidney Int. 89, 147–157 (2016).
Dowson, C. & O’Reilly, S. DNA methylation in fibrosis. Eur. J. Cell Biol. 95, 323–330 (2016).
Zhang, X. et al. DNA methylation regulated gene expression in organ fibrosis. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 2389–2397 (2017).
Dees, C. et al. TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. J. Clin. Invest. 130, 2347–2363 (2020).
Watson, C. J. et al. Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum. Mol. Genet. 23, 2176–2188 (2014).
Sanders, Y. Y. et al. Altered DNA methylation profile in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 186, 525–535 (2012).
Bechtel, W. et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 16, 544–550 (2010).
Zhao, S., Cao, M., Wu, H., Hu, Y. & Xue, X. 5-Aza-2′-deoxycytidine inhibits the proliferation of lung fibroblasts in neonatal rats exposed to hyperoxia. Pediatr. Neonatol. 58, 122–127 (2017).
Dees, C., Chakraborty, D. & Distler, J. H. W. Cellular and molecular mechanisms in fibrosis. Exp. Dermatol. 30, 121–131 (2021).
Robinson, C. M. et al. Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype. Respir. Res. 13, 74 (2012).
Huang, S. K. et al. Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice. Am. J. Pathol. 177, 2245–2255 (2010).
Liu, F. et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J. Cell Biol. 190, 693–706 (2010).
Cisneros, J. et al. Hypermethylation-mediated silencing of p14ARF in fibroblasts from idiopathic pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 303, L295–L303 (2012).
Bernau, K. et al. Selective inhibition of bromodomain-containing protein 4 reduces myofibroblast transdifferentiation and pulmonary fibrosis. Front. Mol. Med. 2, 842558 (2022).
Hu, B., Gharaee-Kermani, M., Wu, Z. & Phan, S. H. Epigenetic regulation of myofibroblast differentiation by DNA methylation. Am. J. Pathol. 177, 21–28 (2010).
Xu, X. et al. Epigenetic balance of aberrant Rasal1 promoter methylation and hydroxymethylation regulates cardiac fibrosis. Cardiovasc. Res. 105, 279–291 (2015).
Chen, X. et al. Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis. Cell Death Dis. 9, 1021 (2018).
Xie, S. A. et al. Matrix stiffness determines the phenotype of vascular smooth muscle cell in vitro and in vivo: role of DNA methyltransferase 1. Biomaterials 155, 203–216 (2018).
Xing, W. J. et al. MRTF‐A and STAT 3 promote MDA‐MB‐231 cell migration via hypermethylating BRSM1. IUBMB Life 67, 202–217 (2015).
Hu, S. et al. NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma. Gastroenterology 163, 449–465 (2022).
Henderson, N. C., Rieder, F. & Wynn, T. A. Fibrosis: from mechanisms to medicines. Nature 587, 555–566 (2020).
El Agha, E. & Thannickal, V. J. The lung mesenchyme in development, regeneration, and fibrosis. J. Clin. Invest. 133, e170498 (2023).
Gieseck, R. L. 3rd, Wilson, M. S. & Wynn, T. A. Type 2 immunity in tissue repair and fibrosis. Nat. Rev. Immunol. 18, 62–76 (2018).
Pakshir, P. & Hinz, B. The big five in fibrosis: macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 68-69, 81–93 (2018).
Forbes, S. J. & Rosenthal, N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat. Med. 20, 857–869 (2014).
Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).
Mori, R., Shaw, T. J. & Martin, P. Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J. Exp. Med. 205, 43–51 (2008).
Cash, J. L. et al. Resolution mediator chemerin15 reprograms the wound microenvironment to promote repair and reduce scarring. Curr. Biol. 24, 1406–1414 (2014).
Knipper, J. A. et al. Interleukin-4 receptor α signaling in myeloid cells controls collagen fibril assembly in skin repair. Immunity 43, 803–816 (2015).
Ploeger, D. T. et al. Cell plasticity in wound healing: paracrine factors of M1/ M2 polarized macrophages influence the phenotypical state of dermal fibroblasts. Cell Commun. Signal. 11, 29 (2013).
Eming, S. A., Wynn, T. A. & Martin, P. Inflammation and metabolism in tissue repair and regeneration. Science 356, 1026–1030 (2017).
Mirza, R., DiPietro, L. A. & Koh, T. J. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am. J. Pathol. 175, 2454–2462 (2009).
MacLeod, A. S. & Mansbridge, J. N. The innate immune system in acute and chronic wounds. Adv. Wound Care 5, 65–78 (2016).
Fritz, J. M. et al. Depletion of tumor-associated macrophages slows the growth of chemically induced mouse lung adenocarcinomas. Front. Immunol. 5, 587 (2014).
Duffield, J. S., Lupher, M., Thannickal, V. J. & Wynn, T. A. Host responses in tissue repair and fibrosis. Annu. Rev. Pathol. 8, 241–276 (2013).
Shook, B. A. et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 362, eaar2971 (2018).
Minutti, C. M., Knipper, J. A., Allen, J. E. & Zaiss, D. M. Tissue-specific contribution of macrophages to wound healing. Semin. Cell Dev. Biol. 61, 3–11 (2017).
Campbell, L., Saville, C. R., Murray, P. J., Cruickshank, S. M. & Hardman, M. J. Local arginase 1 activity is required for cutaneous wound healing. J. Invest. Dermatol. 133, 2461–2470 (2013).
Glim, J. E., Niessen, F. B., Everts, V., van Egmond, M. & Beelen, R. H. Platelet derived growth factor-CC secreted by M2 macrophages induces alpha-smooth muscle actin expression by dermal and gingival fibroblasts. Immunobiology 218, 924–929 (2013).
Lanone, S. et al. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. J. Clin. Invest. 110, 463–474 (2002).
Lodyga, M. et al. Cadherin-11-mediated adhesion of macrophages to myofibroblasts establishes a profibrotic niche of active TGF-β. Sci. Signal. 12, eaao3469 (2019).
Skalli, O. et al. A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation. J. Cell Biol. 103, 2787–2796 (1986).
Zeltz, C. et al. Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins. Semin. Cancer Biol. 62, 166–181 (2020).
Riley, L. A. & Merryman, W. D. Cadherin-11 and cardiac fibrosis: a common target for a common pathology. Cell Signal. 78, 109876 (2021).
Chavula, T., To, S. & Agarwal, S. K. Cadherin-11 and its role in tissue fibrosis. Cell Tissues Organs 212, 293–303 (2023).
Nikoloudaki, G., Creber, K. & Hamilton, D. W. Wound healing and fibrosis: a contrasting role for periostin in skin and the oral mucosa. Am. J. Physiol. Cell Physiol. 318, C1065–C1077 (2020).
Yeo, S. Y. et al. A positive feedback loop bi-stably activates fibroblasts. Nat. Commun. 9, 3016 (2018).
Leask, A. The hard problem: mechanotransduction perpetuates the myofibroblast phenotype in scleroderma fibrosis. Wound Repair Regen. 29, 582–587 (2021).
Ruiz-Villalba, A. et al. Single-cell RNA sequencing analysis reveals a crucial role for CTHRC1 (collagen triple helix repeat containing 1) cardiac fibroblasts after myocardial infarction. Circulation 142, 1831–1847 (2020).
Naba, A. Ten years of extracellular matrix proteomics: accomplishments, challenges, and future perspectives. Mol. Cell Proteom. 22, 100528 (2023).
Bingham, G. C., Lee, F., Naba, A. & Barker, T. H. Spatial-omics: novel approaches to probe cell heterogeneity and extracellular matrix biology. Matrix Biol. 91-92, 152–166 (2020).
Tomasek, J. J., Haaksma, C. J., Schwartz, R. J. & Howard, E. W. Whole animal knockout of smooth muscle alpha-actin does not alter excisional wound healing or the fibroblast-to-myofibroblast transition. Wound Repair Regen. 21, 166–176 (2013).
Arnoldi, R., Chaponnier, C., Gabbiani, G. & Hinz, B. in Muscle: Fundamental Biology and Mechanisms of Disease (ed. Hill, J.) 1183–1195 (Elsevier, 2012).
Chang, S. K., Gu, Z. & Brenner, M. B. Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11. Immunol. Rev. 233, 256–266 (2010).
Tan, C. et al. Soluble Thy-1 reverses lung fibrosis via its integrin-binding motif. JCI Insight 4, e131152 (2019).
Marangoni, R. G. et al. Thy-1 plays a pathogenic role and is a potential biomarker for skin fibrosis in scleroderma. JCI Insight 7, e149426 (2022).
Hudon-David, F., Bouzeghrane, F., Couture, P. & Thibault, G. Thy-1 expression by cardiac fibroblasts: lack of association with myofibroblast contractile markers. J. Mol. Cell Cardiol. 42, 991–1000 (2007).
Schliekelman, M. J. et al. Thy-1+ cancer-associated fibroblasts adversely impact lung cancer prognosis. Sci. Rep. 7, 6478 (2017).
Cao, Y., Wang, X. & Peng, G. SCSA: a cell type annotation tool for single-cell RNA-seq data. Front. Genet. 11, 490 (2020).
Hou, R., Denisenko, E. & Forrest, A. R. R. scMatch: a single-cell gene expression profile annotation tool using reference datasets. Bioinformatics 35, 4688–4695 (2019).
Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017).
Dominguez, C. X. et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 10, 232–253 (2020).
Zhang, W. et al. Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J. Am. Heart Assoc. 4, e001993 (2015).
Madaro, L. et al. Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Nat. Cell Biol. 20, 917–927 (2018).
Gschwandtner, M., Derler, R. & Midwood, K. S. More than just attractive: how CCL2 influences myeloid cell behavior beyond chemotaxis. Front. Immunol. 10, 2759 (2019).
Kouzeli, A. et al. CXCL14 preferentially synergizes with homeostatic chemokine receptor systems. Front. Immunol. 11, 561404 (2020).
Kastenschmidt, J. M. et al. A stromal progenitor and ILC2 niche promotes muscle eosinophilia and fibrosis-associated gene expression. Cell Rep. 35, 108997 (2021).
Kuswanto, W. et al. Poor repair of skeletal muscle in aging mice reflects a defect in local, interleukin-33-dependent accumulation of regulatory T cells. Immunity 44, 355–367 (2016).
Bujak, M. et al. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. Am. J. Pathol. 173, 57–67 (2008).
Turner, N. A. et al. Interleukin-1α stimulates proinflammatory cytokine expression in human cardiac myofibroblasts. Am. J. Physiol. Heart Circ. Physiol. 297, H1117–H1127 (2009).
Acknowledgements
The research of B.H. is supported by a foundation grant from the Canadian Institutes of Health Research (#375597) and support from the John Evans Leadership funds (#36050 and #38861), as well as innovation funds (‘Fibrosis Network, #36349’) from the Canada Foundation for Innovation (CFI) and the Ontario Research Fund (ORF). F.M.V.R. is supported by the Canadian Institutes of Health Research (#38395). T.H.B. is supported by the National Institute of Health (NIH) funds NIH R01-HL130918 and NIH R01-HL155143. The original figures were generated with the assistance of BioRender.
Author information
Authors and Affiliations
Contributions
F.S.Y. and A.E.M. contributed equally to all aspects of the article. All authors contributed to discussion of the content and wrote sections of the article. All authors reviewed and/or edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Molecular Cell Biology thanks the anonymous reviewers for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Glossary
- Arginine–glycine–aspartate (RGD) motif
-
The RGD amino acid sequence is a motif in the latent transforming growth factor-β1 complex and many proteins of the extracellular matrix, where it promotes specific binding of αv integrins; the presence of an adjacent ‘synergy sequence’ in fibronectin also allows integrins αIIbβ3 and α5β1 to bind to RGD.
- Granulation tissue
-
This provisional tissue fills wounds during healing, is rich in various cells and small vessels, and appears in histological cross-sections as ‘granulose’.
- Pericytes
-
Also referred to as perivascular cells, pericytes show fibroblast-like morphology, are closely associated with endothelial cells of the microvasculature and often have progenitor capacity, that is, the ability to differentiate into multiple cell types, including fibroblasts.
- Stiffness
-
Most biological studies dealing with cell, extracellular matrix or tissue ‘stiffness’ refer to the elastic modulus (that is, stress over strain) in pascal, which is a relatively accurate parameter when measured at the length scale of cells and below.
- Strain stiffening
-
In contrast to ideally elastic synthetic polymers, biological polymers such as collagen, fibrin and cytoskeletal filaments get stiffer when they are extended (that is, strained). Strain stiffening protects tissues from overstraining and enables the fibrous collagen around large blood vessels to undergo small peristaltic movements but to cuff the vessel under high blood pressure.
- Stress fibres
-
Contractile bundles composed of actin and myosin filaments as part of the cytoskeleton that are typically formed in response to mechanical stress and often terminate in cell adhesions, which connect to the extracellular matrix or other cells.
- Tropomyosin
-
Tropomyosins are filamentous (F-)actin-binding proteins that regulate actin–myosin interactions in adult striated and smooth muscle, as well as in non-muscle contractile cells such as myofibroblasts.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Younesi, F.S., Miller, A.E., Barker, T.H. et al. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00716-0
Accepted:
Published:
DOI: https://doi.org/10.1038/s41580-024-00716-0
