Review Open Access

Mechanisms of Fibroblast Activation during Fibrotic Tissue Remodeling

Fibrosis. 2024, 2(1), 10002;
Department of Internal Medicine 3–Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, 91054 Erlangen, Germany
Authors to whom correspondence should be addressed.

Received: 31 Dec 2023    Accepted: 22 Feb 2024    Published: 26 Feb 2024   


Fibrosis can occur in almost every organ system. It can occur in single organs, such as in idiopathic pulmonary fibrosis (IPF), or affect multiple organs as in systemic sclerosis (SSc). Fibrotic diseases are recognized as major cause of morbidity and mortality in modern societies due to the dysfunction or loss of function of the affected organs. This dysfunction is caused by progressive deposition of extracellular matrix proteins released by activated fibroblasts. Activation of fibroblasts and differentiation into myofibroblasts is required for physiological tissue remodeling, e.g, during wound healing. Disruption of regulatory mechanisms, however, results in chronic and uncontrolled activity of fibroblasts and myofibroblasts. Intensive research during the past years identified several core pathways of pathophysiological relevance, and described different fibroblast subsets based on their expression profile in fibrotic tissue. Herein, we discuss the molecular changes in fibroblasts leading to persistent activation during fibrotic tissue remodeling with a focus on lung fibrosis and SSc.


Denton CP, Khanna D.  Systemic sclerosis. Lancet 2017, 390, 1685–1699. [Google Scholar]
Wollheim FA.  Classification of systemic sclerosis. Visions and reality. Rheumatology 2005, 44, 1212–1216. [Google Scholar]
Allanore Y, Simms R, Distler O, Trojanowska M, Pope J, Denton CP, et al. Systemic sclerosis. Nat. Rev. Dis. Primers 2015, 1, 15002. [Google Scholar]
Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013, 65, 1953–1962. [Google Scholar]
Wynn TA. Cellular and molecular mechanisms of fibrosis. J. Pathol. 2008, 214, 199–210. [Google Scholar]
Pakshir P, Noskovicova N, Lodyga M, Son DO, Schuster R, Goodwin A, et al. The myofibroblast at a glance. J. Cell Sci. 2020, 133, doi:10.1242/jcs.227900.
Distler JHW, Gyorfi AH, Ramanujam M, Whitfield ML, Konigshoff M, Lafyatis R. Shared and distinct mechanisms of fibrosis. Nat. Rev. Rheumatol. 2019, 15, 705–730. [Google Scholar]
Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat. Rev. Immunol. 2004, 4, 583–594. [Google Scholar]
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell. Biol. 2002, 3, 349–363. [Google Scholar]
Bochaton-Piallat ML, Gabbiani G, Hinz B. The myofibroblast in wound healing and fibrosis: answered and unanswered questions. F1000Res 2016, 5, doi:10.12688/f1000research.8190.1.
Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am. J. Pathol. 2012, 180, 1340–1355. [Google Scholar]
McAnulty RJ. Fibroblasts and myofibroblasts: their source, function and role in disease. Int. J. Biochem. Cell Biol. 2007, 39, 666–671. [Google Scholar]
Mehal WZ, Iredale J, Friedman SL.  Scraping fibrosis: expressway to the core of fibrosis. Nat. Med. 2011, 17, 552–553. [Google Scholar]
Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 2013, 19, 1617–1624. [Google Scholar]
Kim KK, Sheppard D, Chapman HA. TGF-beta1 Signaling and Tissue Fibrosis. Cold Spring Harb. Perspect. Biol. 2018, 10, a022293. [Google Scholar]
Mendoza FA, Jimenez SA. Serine/threonine kinase inhibition as antifibrotic therapy: transforming growth factor-beta and Rho kinase inhibitors. Rheumatology 2022, 61, 1354–1365. [Google Scholar]
Luo K. Signaling Cross Talk between TGF-beta/Smad and Other Signaling Pathways. Cold Spring Harb. Perspect. Biol. 2017, 9, a022137. [Google Scholar]
Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, et al. Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat. Commun. 2012, 3, 735. [Google Scholar]
Dees C, Schlottmann I, Funke R, Distler A, Palumbo-Zerr K, Zerr P, et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann. Rheum. Dis. 2014, 73, 1232–1239. [Google Scholar]
Henderson J, Pryzborski S, Stratton R, O'Reilly S. Wnt antagonist DKK-1 levels in systemic sclerosis are lower in skin but not in blood and are regulated by microRNA33a-3p. Exp. Dermatol. 2021, 30, 162–168. [Google Scholar]
Wei J, Fang F, Lam AP, Sargent JL, Hamburg E, Hinchcliff ME, et al. Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum. 2012, 64, 2734–2745. [Google Scholar]
Bergmann C, Hallenberger L, Chenguiti Fakhouri S, Merlevede B, Brandt A, Dees C, et al. X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc). Ann. Rheum. Dis. 2021, 80, 1048–1056. [Google Scholar]
Wei J, Melichian D, Komura K, Hinchcliff M, Lam AP, Lafyatis R, et al. Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum. 2011, 63, 1707–1717. [Google Scholar]
Shi C, Chen X, Yin W, Sun Z, Hou J, Han X. Wnt8b regulates myofibroblast differentiation of lung-resident mesenchymal stem cells via the activation of Wnt/beta-catenin signaling in pulmonary fibrogenesis. Differentiation 2022, 125, 35–44. [Google Scholar]
Newman DR, Sills WS, Hanrahan K, Ziegler A, Tidd KM, Cook E, et al. Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-beta and WNT7B in Human Lung Fibroblasts. J. Histochem. Cytochem. 2016, 64, 99–111. [Google Scholar]
=Vuga LJ, Ben-Yehudah A, Kovkarova-Naumovski E, Oriss T, Gibson KF, Feghali-Bostwick C, et al. WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. Am. J. Respir. Cell Mol. Biol. 2009, 41, 583–589. [Google Scholar]
Ingham PW, Nakano Y, Seger C. Mechanisms and functions of Hedgehog signalling across the metazoa. Nat. Rev. Genet. 2011, 12, 393–406. [Google Scholar]
Chanda D, Otoupalova E, Smith SR, Volckaert T, De Langhe SP, Thannickal VJ. Developmental pathways in the pathogenesis of lung fibrosis. Mol. Aspects Med. 2019, 65, 56–69. [Google Scholar]
Horn A, Palumbo K, Cordazzo C, Dees C, Akhmetshina A, Tomcik M, et al. Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis Rheum. 2012, 64, 2724–2733. [Google Scholar]
Liang R, Sumova B, Cordazzo C, Mallano T, Zhang Y, Wohlfahrt T, et al. Michalska-Jakubus, et al. The transcription factor GLI2 as a downstream mediator of transforming growth factor-beta-induced fibroblast activation in SSc. Ann. Rheum. Dis. 2017, 76, 756–764. [Google Scholar]
Bray SJ. Notch signalling in context. Nat. Rev. Mol. Cell. Biol. 2016, 17, 722–735. [Google Scholar]
D’Souza B, Meloty-Kapella L, Weinmaster G. Canonical and non-canonical Notch ligands. Curr. Top. Dev. Biol. 2010, 92, 73–129. [Google Scholar]
Dees C, Tomcik M, Zerr P, Akhmetshina A, Horn A, Palumbo K, et al. Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann. Rheum. Dis. 2011, 70, 1304–1310. [Google Scholar]
Dees C, Zerr P, Tomcik M, Beyer C, Horn A, Akhmetshina A, et al. Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis. Arthritis Rheum. 2011, 63, 1396–1404. [Google Scholar]
Kavian N, Servettaz A, Mongaret C, Wang A, Nicco C, Chereau C, et al. Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model. Arthritis Rheum. 2010, 62, 3477–3487. [Google Scholar]
Kiyokawa H, Morimoto M. Notch signaling in the mammalian respiratory system, specifically the trachea and lungs, in development, homeostasis, regeneration, and disease. Dev. Growth Differ. 2020, 62, 67–79. [Google Scholar]
Hu B, Wu Z, Bai D, Liu T, Ullenbruch MR, Phan SH. Mesenchymal deficiency of Notch1 attenuates bleomycin-induced pulmonary fibrosis. Am. J. Pathol. 2015, 185, 3066–3075. [Google Scholar]
Wang YC, Chen Q, Luo JM, Nie J, Meng QH, Shuai W, et al. Notch1 promotes the pericyte-myofibroblast transition in idiopathic pulmonary fibrosis through the PDGFR/ROCK1 signal pathway. Exp. Mol. Med. 2019, 51, 1–11. [Google Scholar]
Weikum ER, Liu X, Ortlund EA. The nuclear receptor superfamily: A structural perspective. Protein Sci. 2018, 27, 1876–1892. [Google Scholar]
Derrett-Smith E, Clark KEN, Shiwen X, Abraham DJ, Hoyles RK, Lacombe O, et al. The pan-PPAR agonist lanifibranor reduces development of lung fibrosis and attenuates cardiorespiratory manifestations in a transgenic mouse model of systemic sclerosis. Arthritis Res. Ther. 2021, 23, 234. [Google Scholar]
Ghosh AK, Bhattacharyya S, Lakos G, Chen SJ, Mori Y, Varga J. Disruption of transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor gamma. Arthritis Rheum. 2004, 50, 1305–1318. [Google Scholar]
Wei, A, Gao Q, Chen F, Zhu X, Chen X, Zhang L, et al. Inhibition of DNA methylation de-represses peroxisome proliferator-activated receptor-gamma and attenuates pulmonary fibrosis. Br. J. Pharmacol. 2022, 179, 1304–1318. [Google Scholar]
Wei J, Ghosh AK, Sargent JL, Komura K, Wu M, Huang QQ, et al. PPARgamma downregulation by TGFss in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis. PLoS ONE 2010, 5, e13778. [Google Scholar]
Ghosh AK, Bhattacharyya S, Wei J, Kim S, Barak Y, Mori Y, et al. Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator. FASEB J. 2009, 23, 2968–2977. [Google Scholar]
Zerr P, Vollath S, Palumbo-Zerr K, Tomcik M, Huang J, Distler A, et al. Vitamin D receptor regulates TGF-beta signalling in systemic sclerosis. Ann. Rheum. Dis. 2015, 74, e20. [Google Scholar]
Tzilas V, Bouros E, Barbayianni I, Karampitsakos T, Kourtidou S, Ntassiou M, et al. Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis. Pulm. Pharmacol. Ther. 2019, 55, 17–24. [Google Scholar]
Avouac J, Pezet S, Gonzalez V, Baudoin L, Cauvet A, Ruiz B, et al. Estrogens Counteract the Profibrotic Effects of TGF-beta and their Inhibition Exacerbates Experimental Dermal Fibrosis. J. Invest. Dermatol. 2020, 140, 593–601. [Google Scholar]
Elhai M, Avouac J, Walker UA, Matucci-Cerinic M, Riemekasten G, Airo P, Hachulla E, et al. A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study. Ann. Rheum. Dis. 2016, 75, 163–169. [Google Scholar]
Aida-Yasuoka K, Peoples C, Yasuoka H, Hershberger P, Thiel K, Cauley JA, et al. Estradiol promotes the development of a fibrotic phenotype and is increased in the serum of patients with systemic sclerosis. Arthritis Res. Ther. 2013, 15, R10. [Google Scholar]
Soldano S, Montagna P, Brizzolara R, Sulli A, Parodi A, Seriolo B, et al. Effects of estrogens on extracellular matrix synthesis in cultures of human normal and scleroderma skin fibroblasts. Ann. N. Y. Acad. Sci. 2010, 1193, 25–29. [Google Scholar]
Brown M, O’Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin. Exp. Immunol. 2019, 195, 310–321. [Google Scholar]
Mutsaers SE, Miles T, Prele CM, Hoyne GF. Emerging role of immune cells as drivers of pulmonary fibrosis. Pharmacol. Ther. 2023, 252, 108562. [Google Scholar]
Fertin C, Nicolas JF, Gillery P, Kalis B, Banchereau J, Maquart FX. Interleukin-4 stimulates collagen synthesis by normal and scleroderma fibroblasts in dermal equivalents. Cell. Mol. Biol. 1991, 37, 823–829. [Google Scholar]
Postlethwaite AE, Holness MA, Katai H, Raghow R. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J. Clin. Invest. 1992, 90, 1479–1485. [Google Scholar]
Sempowski GD, Derdak S, Phipps RP. Interleukin-4 and interferon-gamma discordantly regulate collagen biosynthesis by functionally distinct lung fibroblast subsets. J. Cell. Physiol. 1996, 167, 290–296. [Google Scholar]
Wegrowski Y, Paltot V, Gillery P, Kalis B, Randoux A, Maquart FX. Stimulation of sulphated glycosaminoglycan and decorin production in adult dermal fibroblasts by recombinant human interleukin-4. Biochem. J. 1995, 307, 673–678. [Google Scholar]
Chakraborty D, Sumova B, Mallano T, Chen CW, Distler A, Bergmann C, et al. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nat. Commun. 2017, 8, 1130. [Google Scholar]
Dees C, Tomcik M, Palumbo-Zerr K, Distler A, Beyer C, Lang V, et al. JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor beta in systemic sclerosis. Arthritis Rheum. 2012, 64, 3006–3015. [Google Scholar]
O’Reilly S, Ciechomska M, Cant R, van Laar JM. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-beta (TGF-beta) signaling promoting SMAD3 activation and fibrosis via Gremlin protein. J. Biol. Chem. 2014, 289, 9952–9960. [Google Scholar]
Van Linthout S, Miteva K, Tschope C. Crosstalk between fibroblasts and inflammatory cells. Cardiovasc. Res. 2014, 102, 258–269. [Google Scholar]
van Putten S, Shafieyan Y, Hinz B. Mechanical control of cardiac myofibroblasts. J. Mol. Cell. Cardiol. 2016, 93, 133–142. [Google Scholar]
Ezzo M, Hinz B. Novel approaches to target fibroblast mechanotransduction in fibroproliferative diseases. Pharmacol. Ther. 2023, 250, 108528. [Google Scholar]
Deng Z, Fear MW, Suk Choi Y, Wood FM, Allahham A, Mutsaers SE, et al. The extracellular matrix and mechanotransduction in pulmonary fibrosis. Int. J. Biochem. Cell. Biol. 2020, 126, 105802. [Google Scholar]
Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, et al.  Role of YAP/TAZ in mechanotransduction. Nature 2011, 474, 179–183. [Google Scholar]
Liang M, Yu M, Xia R, Song K, Wang J, Luo J, et al. Yap/Taz Deletion in Gli(+) Cell-Derived Myofibroblasts Attenuates Fibrosis. J. Am. Soc. Nephrol. 2017, 28, 3278–3290. [Google Scholar]
Aravamudhan A, Haak AJ, Choi KM, Meridew JA, Caporarello N, Jones DL, et al. Tschumperlin. TBK1 regulates YAP/TAZ and fibrogenic fibroblast activation. Am. J. Physiol. Lung Cell. Mol. Physiol. 2020, 318, L852–L863. [Google Scholar]
Shi-Wen X, Racanelli M, Ali A, Simon A, Quesnel K, Stratton RJ, et al. Verteporfin inhibits the persistent fibrotic phenotype of lesional scleroderma dermal fibroblasts. J. Cell Commun. Signal 2021, 15, 71–80. [Google Scholar]
Chitturi P, Xu S, Ahmed Abdi B, Nguyen J, Carter DE, Sinha S, et al. Tripterygium wilfordii derivative celastrol, a YAP inhibitor, has antifibrotic effects in systemic sclerosis. Ann. Rheum. Dis. 2023, 82, 1191–1204. [Google Scholar]
Wu D, Wang W, Li X, Yin B, Ma Y. Single-cell sequencing reveals the antifibrotic effects of YAP/TAZ in systemic sclerosis. Int. J. Biochem. Cell. Biol. 2022, 149, 106257. [Google Scholar]
Southern BD, Li H, Mao H, Crish JF, Grove LM, Scheraga RG, et al. A novel mechanoeffector role of fibroblast S100A4 in myofibroblast transdifferentiation and fibrosis. J. Biol. Chem. 2023, 300, 105530. [Google Scholar]
Xu Y, Huang Y, Cheng X, Hu B, Jiang D, Wu L, et al. Mechanotransductive receptor Piezo1 as a promising target in the treatment of fibrosis diseases. Front. Mol. Biosci. 2023, 10, 1270979. [Google Scholar]
Chen H, Qu J, Huang X, Kurundkar A, Zhu L, Yang N, et al. Mechanosensing by the alpha6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis. Nat. Commun. 2016, 7, 12564. [Google Scholar]
Sawant M, Wang F, Koester J, Niehoff A, Nava MM, Lundgren-Akerlund E, et al. Ablation of integrin-mediated cell-collagen communication alleviates fibrosis. Ann. Rheum. Dis. 2023, 82, 1474–1486. [Google Scholar]
Yue B. Biology of the extracellular matrix: an overview. J. Glaucoma 2014, 23, S20–S23. [Google Scholar]
Huang M, Cai G, Baugh LM, Liu Z, Smith A, Watson M, et al. Systemic Sclerosis Dermal Fibroblasts Induce Cutaneous Fibrosis Through Lysyl Oxidase-like 4: New Evidence From Three-Dimensional Skin-like Tissues. Arthritis Rheumatol. 2020, 72, 791–801. [Google Scholar]
Espindola MS, Habiel DM, Coelho AL, Parimon T, Chen P, Mikels-Vigdal A, Hogaboam CM. Translational Studies Reveal the Divergent Effects of Simtuzumab Targeting LOXL2 in Idiopathic Pulmonary Fibrosis. Fibrosis 2023, 1, 10007. [Google Scholar]
Muir AJ, Levy C, Janssen HLA, Montano-Loza AJ, Shiffman ML, Caldwell S, et al. Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease. Hepatology 2019, 69, 684–698. [Google Scholar]
Johnson TS, El-Koraie AF, Skill NJ, Baddour NM, El Nahas AM, Njloma M, et al. Tissue transglutaminase and the progression of human renal scarring. J. Am. Soc. Nephrol. 2003, 14, 2052–2062. [Google Scholar]
Johnson TS, Skill NJ, El Nahas AM, Oldroyd SD, Thomas GL, Douthwaite JA, et al. Transglutaminase transcription and antigen translocation in experimental renal scarring. J. Am. Soc. Nephrol. 1999, 10, 2146–2157. [Google Scholar]
Olsen KC, Sapinoro RE, Kottmann RM, Kulkarni AA, Iismaa SE, Johnson GV, et al. Transglutaminase 2 and its role in pulmonary fibrosis. Am. J. Respir. Crit. Care. Med. 2011, 184, 699–707. [Google Scholar]
Zhou X, Trinh-Minh T, Matei AE, Gyorfi AH, Hong X, Bergmann C, et al. Amelioration of Fibrotic Remodeling of Human 3-Dimensional Full-Thickness Skin by Transglutamase 2 Inhibition. Arthritis Rheumatol. 2023, 75, 1619–1627. [Google Scholar]
Hasaneen NA, Cao J, Pulkoski-Gross A, Zucker S, Foda HD. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) promotes lung fibroblast proliferation, survival and differentiation to myofibroblasts. Respir. Res. 2016, 17, 17. [Google Scholar]
Liu F, Yu F, Lu YZ, Cheng PP, Liang LM, Wang M, et al. Crosstalk between pleural mesothelial cell and lung fibroblast contributes to pulmonary fibrosis. Biochim. Biophys. Acta Mol. Cell. Res. 2020, 1867, 118806. [Google Scholar]
Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Hamaguchi Y, et al. Increased serum soluble CD147 levels in patients with systemic sclerosis: association with scleroderma renal crisis. Clin. Rheumatol. 2012, 31, 835–839. [Google Scholar]
Niwa H, Kanno Y, Shu E, Seishima M. Decrease in matrix metalloproteinase‑3 activity in systemic sclerosis fibroblasts causes alpha2‑antiplasmin and extracellular matrix deposition, and contributes to fibrosis development. Mol. Med. Rep. 2020, 22, 3001–3007. [Google Scholar]
Cinetto F, Ceccato J, Caputo I, Cangiano D, Montini B, Lunardi F, et al. GSK-3 Inhibition Modulates Metalloproteases in a Model of Lung Inflammation and Fibrosis. Front. Mol. Biosci. 2021, 8, 633054. [Google Scholar]
Peng Z, Konai MM, Avila-Cobian LF, Wang M, Mobashery S, Chang M. MMP-1 and ADAM10 as Targets for Therapeutic Intervention in Idiopathic Pulmonary Fibrosis. ACS Pharmacol. Transl. Sci. 2022, 5, 548–554. [Google Scholar]
Hermann A, Goyal R, Jeltsch A. The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J. Biol. Chem. 2004, 279, 48350–48359. [Google Scholar]
Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 2012, 13, 484–492. [Google Scholar]
Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999, 99, 247–257. [Google Scholar]
Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ, et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 2010, 16, 544–550. [Google Scholar]
Dees C, Potter S, Zhang Y, Bergmann C, Zhou X, Luber M, et al. TGF-beta-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. J. Clin. Invest. 2020, 130, 2347–2363. [Google Scholar]
Henderson J, Brown M, Horsburgh S, Duffy L, Wilkinson S, Worrell J, et al. Methyl cap binding protein 2: a key epigenetic protein in systemic sclerosis. Rheumatology 2019, 58, 527–535. [Google Scholar]
Zhang Y, Potter S, Chen CW, Liang R, Gelse K, Ludolph I, et al. Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis. Ann. Rheum. Dis. 2018, 77, 744–751. [Google Scholar]
Malaab M, Renaud L, Takamura N, Zimmerman KD, da Silveira WA, Ramos PS, et al. Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis. Ann. Rheum. Dis. 2022, 81, 268–277. [Google Scholar]
Baker Frost D, da Silveira W, Hazard ES, Atanelishvili I, Wilson RC, Flume J, et al. Differential DNA Methylation Landscape in Skin Fibroblasts from African Americans with Systemic Sclerosis. Genes 2021, 12, 129. [Google Scholar]
Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur. Respir. J. 2005, 25, 552–563. [Google Scholar]
Bhattacharyya S, Ghosh AK, Pannu J, Mori Y, Takagawa S, Chen G, et al. Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor beta. Arthritis Rheum. 2005, 52, 1248–1258. [Google Scholar]
Ghosh AK, Bhattacharyya S, Lafyatis R, Farina G, Yu J, Thimmapaya B, et al. p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-beta: epigenetic feed-forward amplification of fibrosis. J. Invest. Dermatol. 2013, 133, 1302–1310. [Google Scholar]
Zehender A, Li YN, Lin NY, Stefanica A, Nuchel J, Chen CW, et al. TGFbeta promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy. Nat. Commun. 2021, 12, 4404. [Google Scholar]
Kramer M, Dees C, Huang J, Schlottmann I, Palumbo-Zerr K, Zerr P, et al. Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Ann. Rheum. Dis. 2013, 72, 614–620. [Google Scholar]
Maurer B, Distler JH, Distler O. The Fra-2 transgenic mouse model of systemic sclerosis. Vascul. Pharmacol. 2013, 58, 194–201. [Google Scholar]
Bergmann C, Brandt A, Merlevede B, Hallenberger L, Dees C, Wohlfahrt T, et al. The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Ann. Rheum. Dis. 2018, 77, 150–158. [Google Scholar]
Wohlfahrt T, Rauber S, Uebe S, Luber M, Soare A, Ekici A, et al. PU.1 controls fibroblast polarization and tissue fibrosis. Nature 2019, 566, 344–349. [Google Scholar]
Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J. Exp. Med. 2010, 207, 1589–1597. [Google Scholar]
Henderson J, Wilkinson S, Przyborski S, Stratton R, O’Reilly S. microRNA27a-3p mediates reduction of the Wnt antagonist sFRP-1 in systemic sclerosis. Epigenetics 2021, 16, 808–817. [Google Scholar]
Maurer B, Stanczyk J, Jungel A, Akhmetshina A, Trenkmann M, Brock M, et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 2010, 62, 1733–1743. [Google Scholar]
Yao Q, Xing Y, Wang Z, Liang J, Lin Q, Huang M, et al. MiR-16-5p suppresses myofibroblast activation in systemic sclerosis by inhibiting NOTCH signaling. Aging 2020, 13, 2640–2654. [Google Scholar]
Wang Z, Jinnin M, Nakamura K, Harada M, Kudo H, Nakayama W, et al. Long non-coding RNA TSIX is upregulated in scleroderma dermal fibroblasts and controls collagen mRNA stabilization. Exp. Dermatol. 2016, 25, 131–136. [Google Scholar]
Takata M, Pachera E, Frank-Bertoncelj M, Kozlova A, Jungel A, Whitfield ML, et al. OTUD6B-AS1 Might Be a Novel Regulator of Apoptosis in Systemic Sclerosis. Front. Immunol. 2019, 10, 1100. [Google Scholar]
Wasson CW, Abignano G, Hermes H, Malaab M, Ross RL, Jimenez SA, et al. Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH. Ann. Rheum. Dis. 2020, 79, 507–517. [Google Scholar]
Wasson CW, Ross RL, Wells R, Corinaldesi C, Georgiou IC, Riobo-Del Galdo NA, et al. Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts. Arthritis Res. Ther. 2020, 22, 286. [Google Scholar]
Pachera E, Assassi S, Salazar GA, Stellato M, Renoux F, Wunderlin A, et al. Long noncoding RNA H19X is a key mediator of TGF-beta-driven fibrosis. J. Clin. Invest. 2020, 130, 4888–4905. [Google Scholar]
Quiros PM, Mottis A, Auwerx J. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell. Biol. 2016, 17, 213–226. [Google Scholar]
Braga PC, Alves MG, Rodrigues AS, Oliveira PF. Mitochondrial Pathophysiology on Chronic Kidney Disease. Int. J. Mol. Sci. 2022, 23, 1776. [Google Scholar]
Bueno M, Lai YC, Romero Y, Brands J, St Croix CM, Kamga C, et al. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J. Clin. Invest. 2015, 125, 521–538. [Google Scholar]
Jaeger VK, Lebrecht D, Nicholson AG, Wells A, Bhayani H, Gazdhar A, et al. Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis. Sci. Rep. 2019, 9, 5500. [Google Scholar]
Cantanhede IG, Liu H, Liu H, Balbuena Rodriguez V, Shiwen X, Ong VH, et al. Exploring metabolism in scleroderma reveals opportunities for pharmacological intervention for therapy in fibrosis. Front. Immunol. 2022, 13, 1004949. [Google Scholar]
Zhou X, Trinh-Minh T, Tran-Manh C, Giessl A, Bergmann C, Gyorfi AH, et al. Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis. Arthritis Rheumatol. 2022, 74, 871–881. [Google Scholar]
Zhang M, Tong Z, Wang Y, Fu W, Meng Y, Huang J, et al. Relationship between ferroptosis and mitophagy in renal fibrosis: a systematic review. J. Drug Target. 2023, 31, 858–866. [Google Scholar]
Patel AS, Song JW, Chu SG, Mizumura K, Osorio JC, Shi Y, et al. Epithelial cell mitochondrial dysfunction and PINK1 are induced by transforming growth factor-beta1 in pulmonary fibrosis. PLoS ONE 2015, 10, e0121246. [Google Scholar]
Gazdhar A, Lebrecht D, Roth M, Tamm M, Venhoff N, Foocharoen C, et al. Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis. Sci. Rep. 2014, 4, 5336. [Google Scholar]
Xiao H, Xie Y, Xi K, Xie J, Liu M, Zhang Y, et al. Targeting Mitochondrial Sirtuins in Age-Related Neurodegenerative Diseases and Fibrosis. Aging Dis. 2023, 14, 1583–1605. [Google Scholar]
Sosulski ML, Gongora R, Feghali-Bostwick C, Lasky JA, Sanchez CG. Sirtuin 3 Deregulation Promotes Pulmonary Fibrosis. J. Gerontol. A Biol. Sci. Med. Sci. 2017, 72, 595–602. [Google Scholar]
Zhou T, Lin W, Lin S, Zhong Z, Luo Y, Lin Z, et al. Association of Nuclear Receptor Coactivators with Hypoxia-Inducible Factor-1alpha in the Serum of Patients with Chronic Kidney Disease. Biomed. Res. Int. 2020, 2020, 1587915. [Google Scholar]
Tarin D, Croft CB. Ultrastructural features of wound healing in mouse skin. J. Anat. 1969, 105, 189–190. [Google Scholar]
LeBleu VS, Neilson EG. Origin and functional heterogeneity of fibroblasts. FASEB J. 2020, 34, 3519–3536. [Google Scholar]
Franks JM, Martyanov V, Cai G, Wang Y, Li Z, Wood TA, et al. A Machine Learning Classifier for Assigning Individual Patients With Systemic Sclerosis to Intrinsic Molecular Subsets. Arthritis Rheumatol. 2019, 71, 1701–1710. [Google Scholar]
Driskell RR, Lichtenberger BM, Hoste E, Kretzschmar K, Simons BD, Charalambous M, et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 2013, 504, 277–281. [Google Scholar]
Korosec A, Frech S, Gesslbauer B, Vierhapper M, Radtke C, Petzelbauer P, et al. Lineage Identity and Location within the Dermis Determine the Function of Papillary and Reticular Fibroblasts in Human Skin. J. Invest. Dermatol. 2019, 139, 342–351. [Google Scholar]
Mastrogiannaki M, Lichtenberger BM, Reimer A, Collins CA, Driskell RR, Watt FM. beta-Catenin Stabilization in Skin Fibroblasts Causes Fibrotic Lesions by Preventing Adipocyte Differentiation of the Reticular Dermis. J. Invest. Dermatol. 2016, 136, 1130–1142. [Google Scholar]
Marangoni RG, Datta P, Paine A, Duemmel S, Nuzzo M, Sherwood L, et al. Thy-1 plays a pathogenic role and is a potential biomarker for skin fibrosis in scleroderma. JCI Insight. 2022, 7, 149426. [Google Scholar]
Tan C, Jiang M, Wong SS, Espinoza CR, Kim C, Li X, et al. Soluble Thy-1 reverses lung fibrosis via its integrin-binding motif. JCI Insight. 2019, 4, 131152. [Google Scholar]
Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 2015, 348, aaa2151. [Google Scholar]
Jiang D, Correa-Gallegos D, Christ S, Stefanska A, Liu J, Ramesh P, et al. Two succeeding fibroblastic lineages drive dermal development and the transition from regeneration to scarring. Nat. Cell. Biol. 2018, 20, 422–431. [Google Scholar]
Gyorfi AH, Matei AE, Fuchs M, Liang C, Rigau AR, Hong X, et al. Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation. J. Exp. Med. 2021, 218, e20201916. [Google Scholar]
Tabib T, Morse C, Wang T, Chen W, Lafyatis R. SFRP2/DPP4 and FMO1/LSP1 Define Major Fibroblast Populations in Human Skin. J. Invest. Dermatol. 2018, 138, 802–810. [Google Scholar]
Tsukui T, Sun KH, Wetter JB, Wilson-Kanamori JR, Hazelwood LA, Henderson NC, et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat. Commun. 2020, 11, 1920. [Google Scholar]
Xie T, Wang Y, Deng N, Huang G, Taghavifar F, Geng Y, et al. Single-Cell Deconvolution of Fibroblast Heterogeneity in Mouse Pulmonary Fibrosis. Cell Rep. 2018, 22, 3625–3640. [Google Scholar]
Buechler MB, Pradhan RN, Krishnamurty AT, Cox C, Calviello AK, Wang AW, et al. Cross-tissue organization of the fibroblast lineage. Nature 2021, 593, 575–579. [Google Scholar]
Seguro Paula F, Delgado Alves J. The role of the Notch pathway in the pathogenesis of systemic sclerosis: clinical implications. Expert. Rev. Clin. Immunol. 2021, 17, 1257–1267. [Google Scholar]
Leask A, Naik A, Stratton RJ. Back to the future: targeting the extracellular matrix to treat systemic sclerosis. Nat. Rev. Rheumatol. 2023, 19, 713–723. [Google Scholar]
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