ECM formation and degradation during fibrosis, repair, and regeneration (original) (raw)

• Reuten, R., Mayorca-Guiliani, A. E. & Erler, J. T. Matritecture: mapping the extracellular matrix architecture during health and disease. Matrix Biol. 14, 100102 (2022).
  Article CAS Google Scholar
• Naba, A. et al. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol. Cell. Proteom. 11, M111.014647 (2012).
  Article Google Scholar
• Hynes, R. O. & Naba, A. Overview of the matrisome–an inventory of extracellular matrix constituents and functions. Cold Spring Harb. Perspect. Biol. 4, a004903 (2012).
  Article PubMed PubMed Central Google Scholar
• Bhatia, H. S. et al. Spatial proteomics in three-dimensional intact specimens. Cell 185, 5040–5058.e19 (2022).
  Article CAS PubMed Google Scholar
• Mayorca-Guiliani, A. E. et al. ISDoT: In situ decellularization of tissues for high-resolution imaging and proteomic analysis of native extracellular matrix. Nat. Med. 23, 890–898 (2017).
  Article CAS PubMed Google Scholar
• Mayorca-Guiliani, A. E. et al. Decellularization and antibody staining of mouse tissues to map native extracellular matrix structures in 3D. Nat. Protoc. 14, 3395–3425 (2019).
  Article CAS PubMed Google Scholar
• Li, J. et al. Spatially resolved proteomic map shows that extracellular matrix regulates epidermal growth. Nat. Commun. 13, 4012 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Tsutsui, K. et al. Mapping the molecular and structural specialization of the skin basement membrane for inter-tissue interactions. Nat. Commun. 12, 2577 (2021).
  Article CAS PubMed PubMed Central Google Scholar
• Pozzi, A., Yurchenco, P. D. & Iozzo, R. V. The nature and biology of basement membranes. Matrix Biol. 57–58, 1–11 (2017).
  Article PubMed Google Scholar
• Reuten, R. et al. Basement membrane stiffness determines metastases formation. Nat. Mater. 20, 892–903 (2021).
  Article CAS PubMed Google Scholar
• He, Y., Sardar, S., Bay-Jensen, A. C., Port, H. & Karsdal, M. A. Type IX collagen. In Biochemistry of Collagens, Laminins and Elastin 89–95. https://doi.org/10.1016/B978-0-443-15617-5.00034-2 (Elsevier, 2024).
• Chen, M. et al. Restoration of type VII collagen expression and function in dystrophic epidermolysis bullosa. Nat. Genet. 32, 670–675 (2002).
  Article CAS PubMed Google Scholar
• Patten, J. & Wang, K. Fibronectin in development and wound healing. Adv. Drug Deliv. Rev. 170, 353–368 (2021).
  Article CAS PubMed Google Scholar
• Dalton, C. J. & Lemmon, C. A. Fibronectin: molecular structure, fibrillar structure and mechanochemical signaling. Cells 10, 2443 (2021).
  Article CAS PubMed PubMed Central Google Scholar
• Moretti, L., Stalfort, J., Barker, T. H. & Abebayehu, D. The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation. J. Biol. Chem. 298, 101530 (2022).
  Article CAS PubMed Google Scholar
• Barker, H. E., Cox, T. R. & Erler, J. T. The rationale for targeting the LOX family in cancer. Nat. Rev. Cancer 12, 540–552 (2012).
  Article CAS PubMed Google Scholar
• Lyu, C. et al. Advanced glycation end-products as mediators of the aberrant crosslinking of extracellular matrix in scarred liver tissue. Nat. Biomed. Eng. 7, 1437–1454 (2023).
  Article PubMed Google Scholar
• Fan, W. et al. Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver. Nature 626, 635–642 (2024).
  Article CAS PubMed PubMed Central Google Scholar
• Maller, O. et al. Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. Nat. Mater. 20, 548–559 (2021).
  Article CAS PubMed Google Scholar
• Schuppan, D., Ruehl, M., Somasundaram, R. & Hahn, E. G. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis. 21, 351–372 (2001).
  Article CAS PubMed Google Scholar
• Somasundaram, R. & Schuppan, D. Type I, II, III, IV, V, and VI collagens serve as extracellular ligands for the isoforms of platelet-derived growth factor (AA, BB, and AB). J. Biol. Chem. 271, 26884–26891 (1996).
  Article CAS PubMed Google Scholar
• Schuppan, D. et al. Collagens in the liver extracellular matrix bind hepatocyte growth factor. Gastroenterology 114, 139–152 (1998).
  Article CAS PubMed Google Scholar
• Ruehl, M. et al. The epithelial mitogen keratinocyte growth factor binds to collagens via the consensus sequence glycine-proline-hydroxyproline. J. Biol. Chem. 277, 26872–26878 (2002).
  Article CAS PubMed Google Scholar
• Somasundaram, R. et al. Collagens serve as an extracellular store of bioactive interleukin 2. J. Biol. Chem. 275, 38170–38175 (2000).
  Article CAS PubMed Google Scholar
• Somasundaram, R. et al. Interstitial collagens I, III, and VI sequester and modulate the multifunctional cytokine oncostatin M. J. Biol. Chem. 277, 3242–3246 (2002).
  Article CAS PubMed Google Scholar
• Rafaeva, M. et al. Modeling metastatic colonization in a decellularized organ scaffold-based perfusion bioreactor. Adv. Health. Mater. 11, e2100684 (2022).
  Article Google Scholar
• Karsdal, M. A. et al. The good and the bad collagens of fibrosis—their role in signaling and organ function. Adv. Drug Deliv. Rev. 121, 43–56 (2017).
  Article CAS PubMed Google Scholar
• Maquart, F. X. & Monboisse, J. C. Extracellular matrix and wound healing. Pathol. Biol. 62, 91–95 (2014).
  Article CAS PubMed Google Scholar
• Karsdal, M. A. et al. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G807–G830 (2015).
  Article PubMed PubMed Central Google Scholar
• Sun, K. et al. Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nat. Commun. 5, 3485 (2014).
  Article PubMed Google Scholar
• O’Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).
  Article PubMed Google Scholar
• Yamaguchi, Y. et al. A peptide derived from endostatin ameliorates organ fibrosis. Sci. Transl. Med 4, 136ra71 (2012).
  Article PubMed PubMed Central Google Scholar
• Hamano, Y. & Kalluri, R. Tumstatin, the NC1 domain of alpha3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth. Biochem Biophys. Res Commun. 333, 292–298 (2005).
  Article CAS PubMed Google Scholar
• Cox, T. R. The matrix in cancer. Nat. Rev. Cancer 21, 217–238 (2021).
  Article CAS PubMed Google Scholar
• Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 3, a005058–a005058 (2011).
  Article PubMed PubMed Central Google Scholar
• Brown, G. T. & Kleiner, D. E. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism 65, 1080–1086 (2016).
  Article CAS PubMed Google Scholar
• Bissell, M. J. & Hines, W. C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med 17, 320–329 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science (1979) 326, 1216–1219 (2009).
  CAS Google Scholar
• Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem. Cell Lineage Specif. Cell 126, 677–689 (2006).
  CAS Google Scholar
• Discher, D. E., Janmey, P. & Wang, Y. Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005).
  Article CAS PubMed Google Scholar
• Massagué, J. & Sheppard, D. TGF-β signaling in health and disease. Cell 186, 4007–4037 (2023).
  Article PubMed PubMed Central Google Scholar
• Huang, J. et al. Fibulin-4 deficiency results in ascending aortic aneurysms. Circ. Res 106, 583–592 (2010).
  Article CAS PubMed Google Scholar
• McLaughlin, P. J. et al. Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice. Hum. Mol. Genet 16, 3059–3070 (2007).
  Article CAS PubMed Google Scholar
• Massam-Wu, T. et al. Assembly of fibrillin microfibrils governs extracellular deposition of latent TGFβ. J. Cell Sci. 123, 3006–3018 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Klingberg, F. et al. The ED-A domain enhances the capacity of fibronectin to store latent TGF-β binding protein-1 in the fibroblast matrix. J. Cell Sci. https://doi.org/10.1242/jcs.201293 (2018).
• Horiguchi, M., Ota, M. & Rifkin, D. B. Matrix control of transforming growth factor- function. J. Biochem. 152, 321–329 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Schaefer, L. et al. Small proteoglycans in human diabetic nephropathy: discrepancy between glomerular expression and protein accumulation of decorin, biglycan, lumican, and fibromodulin. FASEB J. 15, 559–561 (2001).
  Article CAS PubMed Google Scholar
• Ferrara, N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol. Biol. Cell 21, 687–690 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Birch, H. L. Extracellular matrix and ageing. 169–190. https://doi.org/10.1007/978-981-13-2835-0_7 (2018).
• Jiang, D. et al. Injury triggers fascia fibroblast collective cell migration to drive scar formation through N-cadherin. Nat. Commun. 11, 5653 (2020).
  Article CAS PubMed PubMed Central Google Scholar
• Correa-Gallegos, D. et al. Patch repair of deep wounds by mobilized fascia. Nature 576, 287–292 (2019).
  Article CAS PubMed Google Scholar
• Baer, J. M. et al. Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC. Nat. Immunol. 24, 1443–1457 (2023).
  Article CAS PubMed PubMed Central Google Scholar
• Dey, S. et al. Loss of miR-29a/b1 promotes inflammation and fibrosis in acute pancreatitis. JCI Insight 6, (2021).
• Panizo, S. et al. Fibrosis in chronic kidney disease: pathogenesis and consequences. Int. J. Mol. Sci. 22, 408 (2021).
  Article CAS PubMed PubMed Central Google Scholar
• Tanwar, S., Rhodes, F., Srivastava, A., Trembling, P. M. & Rosenberg, W. M. Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C. World J. Gastroenterol. 26, 109–133 (2020).
  Article CAS PubMed PubMed Central Google Scholar
• Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med 25, 1822–1832 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Zhao, X., Kwan, J. Y. Y., Yip, K., Liu, P. P. & Liu, F.-F. Targeting metabolic dysregulation for fibrosis therapy. Nat. Rev. Drug Discov. 19, 57–75 (2020).
  Article CAS PubMed Google Scholar
• Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Henderson, N. C., Rieder, F. & Wynn, T. A. Fibrosis: from mechanisms to medicines. Nature 587, 555–566 (2020).
  Article CAS PubMed PubMed Central Google Scholar
• Simon, A. & Tanaka, E. M. Limb regeneration. WIREs Dev. Biol. 2, 291–300 (2013).
  Article Google Scholar
• Godwin, J., Kuraitis, D. & Rosenthal, N. Extracellular matrix considerations for scar-free repair and regeneration: insights from regenerative diversity among vertebrates. Int J. Biochem Cell Biol. 56, 47–55 (2014).
  Article CAS PubMed Google Scholar
• Singh, S. et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin. Gastroenterol. Hepatol. 13, 643–654.e9 (2015).
  Article PubMed Google Scholar
• Raghu, G. et al. Diagnosis of idiopathic pulmonary fibrosis. an official ATS/ERS/JRS/ALAT clinical practice guideline. Am. J. Respir. Crit. Care Med. 198, e44–e68 (2018).
  Article PubMed Google Scholar
• Siddiqui, M. S. et al. Vibration-controlled transient elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 17, 156–163.e2 (2019).
  Article PubMed Google Scholar
• Sanyal, A. J. et al. Diagnostic performance of circulating biomarkers for non-alcoholic steatohepatitis. Nat. Med 29, 2656–2664 (2023).
  Article CAS PubMed PubMed Central Google Scholar
• Bihlet, A. R. et al. Clinical drug development using dynamic biomarkers to enable personalized health care in COPD. Chest 148, 16–23 (2015).
  Article PubMed Google Scholar
• Vali, Y. et al. Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study. Lancet Gastroenterol. Hepatol. 8, 714–725 (2023).
  Article CAS PubMed Google Scholar
• Rasmussen, D. G. K. et al. Endotrophin is a risk marker of complications in CANagliflozin cardioVascular Assessment Study (CANVAS): a randomized controlled trial. Cardiovasc. Diabetol. 21, 261 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Borisov, A. N., Kutz, A., Christ, E. R., Heim, M. H. & Ebrahimi, F. Canagliflozin and metabolic associated fatty liver disease in patients with diabetes mellitus: new insights from CANVAS. J. Clin. Endocrinol. Metab. 108, 2940–2949 (2023).
  Article CAS PubMed PubMed Central Google Scholar
• Harrison, S. A. et al. Effects of resmetirom on noninvasive endpoints in a 36‐week phase 2 active treatment extension study in patients with NASH. Hepatol. Commun. 5, 573–588 (2021).
  Article CAS PubMed PubMed Central Google Scholar
• Mehal, W. Z., Iredale, J. & Friedman, S. L. Scraping fibrosis: expressway to the core of fibrosis. Nat. Med. 17, 552–553 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Roh, H. C. et al. Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling. Mol. Metab. 42, 101086 (2020).
  Article CAS PubMed PubMed Central Google Scholar
• Zhao, Z. et al. TGF-β promotes pericyte-myofibroblast transition in subretinal fibrosis through the Smad2/3 and Akt/mTOR pathways. Exp. Mol. Med. 54, 673–684 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Zou, F., Li, Y., Zhang, S. & Zhang, J. DP1 (Prostaglandin D 2 Receptor 1) activation protects against vascular remodeling and vascular smooth muscle cell transition to myofibroblasts in angiotensin II–induced hypertension in mice. Hypertension 79, 1203–1215 (2022).
  Article CAS PubMed Google Scholar
• Little, K. et al. Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration. J. Neuroinflammation 17, 355 (2020).
  Article CAS PubMed PubMed Central Google Scholar
• Xu, R. et al. Mesenchymal stem cells reversibly de-differentiate myofibroblasts to fibroblast-like cells by inhibiting the TGF-β-SMAD2/3 pathway. Mol. Med. 29, 59 (2023).
  Article CAS PubMed PubMed Central Google Scholar
• Lovisa, S. et al. Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis. Sci. Signal 13, 998–1009 (2020).
  Article Google Scholar
• Lovisa, S. et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat. Med. 21, 998–1009 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Younesi, F. S., Miller, A. E., Barker, T. H., Rossi, F. M. V. & Hinz, B. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-024-00716-0 (2024).
• Ezzo, M. & Hinz, B. Novel approaches to target fibroblast mechanotransduction in fibroproliferative diseases. Pharm. Ther. 250, 108528 (2023).
  Article CAS Google Scholar
• Hinz, B. The extracellular matrix and transforming growth factor-β1: Tale of a strained relationship. Matrix Biol. 47, 54–65 (2015).
  Article CAS PubMed Google Scholar
• Sobierajska, K., Wawro, M. E. & Niewiarowska, J. Oxidative stress enhances the TGF-β2-RhoA-MRTF-A/B axis in cells entering endothelial-mesenchymal transition. Int. J. Mol. Sci. 23, 2062 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Alharthi, A., Verma, A., Sabbineni, H., Adil, M. S. & Somanath, P. R. Distinct effects of pharmacological inhibition of stromelysin1 on endothelial‐to‐mesenchymal transition and myofibroblast differentiation. J. Cell Physiol. 236, 5147–5161 (2021).
  Article CAS PubMed Google Scholar
• Shiju, T. M., Sampaio, L. P., Martinez, V. V., Hilgert, G. S. L. & Wilson, S. E. Transforming growth factor beta-3 localization in the corneal response to epithelial-stromal injury and effects on corneal fibroblast transition to myofibroblasts. Exp. Eye Res. 235, 109631 (2023).
  Article CAS PubMed Google Scholar
• Kolosova, I., Nethery, D. & Kern, J. A. Role of Smad2/3 and p38 MAP kinase in TGF‐β1‐induced epithelial–mesenchymal transition of pulmonary epithelial cells. J. Cell Physiol. 226, 1248–1254 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, X. et al. Amelioration of fibrotic remodeling of human 3‐dimensional full‐thickness skin by transglutamase 2 inhibition. Arthritis Rheumatol. 75, 1619–1627 (2023).
  Article CAS PubMed Google Scholar
• Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Nguyen, X.-X. et al. Lysyl oxidase directly contributes to extracellular matrix production and fibrosis in systemic sclerosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 320, L29–L40 (2021).
  Article CAS PubMed Google Scholar
• Coelho, N. M. et al. Discoidin domain receptor 1 mediates myosin-dependent collagen contraction. Cell Rep. 18, 1774–1790 (2017).
  Article CAS PubMed Google Scholar
• Zhan, L. & Li, J. The role of TRPV4 in fibrosis. Gene 642, 1–8 (2018).
  Article CAS PubMed Google Scholar
• Parichatikanond, W., Duangrat, R. & Mangmool, S. Gαq protein-biased ligand of angiotensin II type 1 receptor mediates myofibroblast differentiation through TGF-β1/ERK axis in human cardiac fibroblasts. Eur. J. Pharm. 951, 175780 (2023).
  Article CAS Google Scholar
• Razinia, Z. et al. Stiffness-dependent motility and proliferation uncoupled by deletion of CD44. Sci. Rep. 7, 16499 (2017).
  Article PubMed PubMed Central Google Scholar
• Cain, S. A., Woods, S., Singh, M., Kimber, S. J. & Baldock, C. ADAMTS6 cleaves the large latent TGFβ complex and increases the mechanotension of cells to activate TGFβ. Matrix Biol. 114, 18–34 (2022).
  Article CAS PubMed Google Scholar
• Rose, K. W. J., Taye, N., Karoulias, S. Z. & Hubmacher, D. Regulation of ADAMTS proteases. Front. Mol.Biosci. 8, (2021).
• Noda, K. et al. Latent TGF-β binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. Proc. Natl. Acad. Sci. USA 110, 2852–2857 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Camarena, V. et al. ADAMTSL2 mutations determine the phenotypic severity in geleophysic dysplasia. JCI Insight 110, 2852-2857 (2024).
• Corey, K. E. et al. ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD. J. Hepatol. 76, 25–33 (2022).
  Article CAS PubMed Google Scholar
• Dagoneau, N. et al. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am. J. Hum. Genet. 75, 801–806 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Aoki, F. & Kojima, I. Therapeutic potential of follistatin to promote tissue regeneration and prevent tissue fibrosis. Endocr. J. 54, 849–854 (2007).
  Article CAS PubMed Google Scholar
• Innis, C. A. & Hyvönen, M. Crystal structures of the heparan sulfate-binding domain of follistatin. Insights into ligand binding. J. Biol. Chem. 278, 39969–39977 (2003).
  Article CAS PubMed Google Scholar
• Kiagiadaki, F. et al. Activin-A causes Hepatic stellate cell activation via the induction of TNFα and TGFβ in Kupffer cells. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 891–899 (2018).
  Article CAS PubMed Google Scholar
• Patella, S., Phillips, D. J., Tchongue, J., de Kretser, D. M. & Sievert, W. Follistatin attenuates early liver fibrosis: effects on hepatic stellate cell activation and hepatocyte apoptosis. Am. J. Physiol.-Gastrointest. Liver Physiol. 290, G137–G144 (2006).
  Article CAS PubMed Google Scholar
• Nordholm, A. et al. Activin A inhibition reduces kidney fibrosis and normalizes bone abnormalities in AKI. J. Am. Soc. Nephrol. 35 (2024).
• Maeshima, A. et al. Follistatin, an activin antagonist, ameliorates renal interstitial fibrosis in a rat model of unilateral ureteral obstruction. Biomed. Res. Int. 2014, 376191 (2014).
  Article PubMed PubMed Central Google Scholar
• Mendell, J. R. et al. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol. Ther. 23, 192–201 (2015).
  Article CAS PubMed Google Scholar
• Di Rocco, M. et al. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial. Nat. Med 29, 2615–2624 (2023).
  Article PubMed PubMed Central Google Scholar
• Hoeper, M. M. et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N. Engl. J. Med. 388, 1478–1490 (2023).
  Article CAS PubMed Google Scholar
• Nusse, R. & Varmus, H. E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99–109 (1982).
  Article CAS PubMed Google Scholar
• Somanader, D. V. N., Zhao, P., Widdop, R. E. & Samuel, C. S. The involvement of the Wnt/β-catenin signaling cascade in fibrosis progression and its therapeutic targeting by relaxin. Biochem Pharm. 223, 116130 (2024).
  Article CAS PubMed Google Scholar
• Froidure, A. et al. Chaotic activation of developmental signalling pathways drives idiopathic pulmonary fibrosis. Eur. Respir. Rev. 29, 190140 (2020).
• Skronska-Wasek, W., Gosens, R., Königshoff, M. & Baarsma, H. A. WNT receptor signalling in lung physiology and pathology. Pharm. Ther. 187, 150–166 (2018).
  Article CAS Google Scholar
• Kneidinger, N. et al. Activation of the WNT/β-catenin pathway attenuates experimental emphysema. Am. J. Respir. Crit. Care Med. 183, 723–733 (2011).
  Article CAS PubMed Google Scholar
• Blyszczuk, P. et al. Transforming growth factor-β-dependent Wnt secretion controls myofibroblast formation and myocardial fibrosis progression in experimental autoimmune myocarditis. Eur. Heart J. ehw116, https://doi.org/10.1093/eurheartj/ehw116 (2016).
• Gurney, A. et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc. Natl. Acad. Sci. USA 109, 11717–11722 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Li, S.-S. et al. Targeting the Wnt/β-catenin signaling pathway as a potential therapeutic strategy in renal tubulointerstitial fibrosis. Front. Pharmacol. 12 (2021).
• Gehrke, A. R. et al. Acoel genome reveals the regulatory landscape of whole-body regeneration. Science 363, eaau6173 (2019).
• Mitoh, S. & Yusa, Y. Extreme autotomy and whole-body regeneration in photosynthetic sea slugs. Curr. Biol. 31, R233–R234 (2021).
  Article CAS PubMed Google Scholar
• Gerber, T. et al. Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration. Science 362, eaaq0681 (2018).
• Wei, X. et al. Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration. Science 377, eabp9444 (2022).
• Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science (1979) 298, 2188–2190 (2002).
  CAS Google Scholar
• Stewart, S., Tsun, Z.-Y. & Belmonte, J. C. I. A histone demethylase is necessary for regeneration in zebrafish. Proc. Natl. Acad. Sci. USA 106, 19889–19894 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Brown, A. C. et al. Fibrin network changes in neonates after cardiopulmonary bypass. Anesthesiology 124, 1021–1031 (2016).
  Article CAS PubMed Google Scholar
• Leung, A., Crombleholme, T. M. & Keswani, S. G. Fetal wound healing. Curr. Opin. Pediatr. 24, 371–378 (2012).
  Article PubMed PubMed Central Google Scholar
• Xu, L. et al. Transforming growth factor β3 attenuates the development of radiation-induced pulmonary fibrosis in mice by decreasing fibrocyte recruitment and regulating IFN-γ/IL-4 balance. Immunol. Lett. 162, 27–33 (2014).
  Article CAS PubMed Google Scholar
• Singh, K., Sachan, N., Ene, T., Dabovic, B. & Rifkin, D. Latent transforming growth factor β binding protein 3 controls adipogenesis. Matrix Biol. 112, 155–170 (2022).
  Article CAS PubMed Google Scholar
• Klingberg, F. et al. Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation. J. Cell Biol. 207, 283–297 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Xia, H. et al. Tissue repair and regeneration with endogenous stem cells. Nat. Rev. Mater. 3, 174–193 (2018).
  Article CAS Google Scholar
• Mascharak, S. et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science 372, eaba2374 (2021).
• Monaghan-Benson, E., Aureille, J. & Guilluy, C. ECM stiffness regulates lung fibroblast survival through RasGRF1-dependent signaling. J. Biol. Chem. 301, 108161 (2025).
  Article CAS PubMed PubMed Central Google Scholar
• Jiang, C. et al. Collagen signaling and matrix stiffness regulate multipotency in glandular epithelial stem cells in mice. Nat. Commun. 15, 10482 (2024).
  Article CAS PubMed PubMed Central Google Scholar
• Paranjpe, S. et al. Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology 64, 1711–1724 (2016).
  Article CAS PubMed Google Scholar
• Michalopoulos, G. K. Liver regeneration. J. Cell. Physiol. 213, 286–300 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• French, B. A. & Holmes, J. W. Implications of scar structure and mechanics for post-infarction cardiac repair and regeneration. Exp. Cell Res. 376, 98–103 (2019).
  Article CAS PubMed Google Scholar
• Rudolph, K. L. et al. Differential regulation of extracellular matrix synthesis during liver regeneration after partial hepatectomy in rats. Hepatology 30, 1159–1166 (1999).
  Article CAS PubMed Google Scholar
• Drixler, T. A. et al. Plasminogen mediates liver regeneration and angiogenesis after experimental partial hepatectomy. Br. J. Surg. 90, 1384–1390 (2003).
  Article CAS PubMed Google Scholar
• Zhou, B. et al. Matrix metalloproteinases-9 deficiency impairs liver regeneration through epidermal growth factor receptor signaling in partial hepatectomy mice. J. Surg. Res. 197, 201–209 (2015).
  Article CAS PubMed Google Scholar
• Sparrelid, E. et al. Serial assessment of growth factors associated with liver regeneration in patients operated with associating liver partition and portal vein ligation for staged hepatectomy. Eur. Surg. Res. 59, 72–82 (2018).
  Article CAS PubMed Google Scholar
• Nejak-Bowen, K., Orr, A., Bowen, W. C. & Michalopoulos, G. K. Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy. PLoS ONE 8, e59836 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Matchett, K. P. et al. Multimodal decoding of human liver regeneration. Nature https://doi.org/10.1038/s41586-024-07376-2 (2024).
• Volk, A., Michalopoulos, G., Weidner, M. & Gebhardt, R. Different proliferative responses of periportal and pericentral rat hepatocytes to hepatocyte growth factor. Biochem. Biophys. Res. Commun. 207, 578–584 (1995).
  Article CAS PubMed Google Scholar
• Wei, Y. et al. Liver homeostasis is maintained by midlobular zone 2 hepatocytes. Science 371, eabb1625 (2021).
• Gallai, M. et al. Proteoglycan gene expression in rat liver after partial hepatectomy. Biochem. Biophys. Res. Commun. 228, 690–694 (1996).
  Article CAS PubMed Google Scholar
• Lassailly, G. et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology 159, 1290–1301.e5 (2020).
  Article PubMed Google Scholar
• Klein, S. et al. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology 130, 1564–1572 (2006).
  Article CAS PubMed Google Scholar
• Lefere, S. et al. Bariatric surgery and the liver—mechanisms, benefits, and risks. Obes. Rev. 22, e13294 (2021).
• Marcellin, P. et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 381, 468–475 (2013).
  Article CAS PubMed Google Scholar
• Rockey, D. C. & Friedman, S. L. Fibrosis regression after eradication of hepatitis C virus: from bench to bedside. Gastroenterology 160, 1502–1520.e1 (2021).
  Article CAS PubMed Google Scholar
• Harrison, S. A. et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N. Engl. J. Med. 390, 497–509 (2024).
  Article PubMed Google Scholar
• Sanyal, A. J. et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2401755 (2024).
• Loomba, R. et al. Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH. N. Engl. J. Med. 389, 998–1008 (2023).
  Article CAS PubMed PubMed Central Google Scholar
• Roehlen, N. et al. A monoclonal antibody targeting nonjunctional claudin-1 inhibits fibrosis in patient-derived models by modulating cell plasticity. Sci. Transl. Med. 14, eabj4221 (2022).
• Vali, Y. et al. Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: A systematic review and meta-analysis. J. Hepatol. 73, 252–262 (2020).
  Article PubMed Google Scholar
• Nielsen, M. J. et al. Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C. Liver Int. 35, 429–437 (2015).
  Article CAS PubMed Google Scholar
• Harrison, S. A. et al. Effects of resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH. Hepatol. Commun. 5, 573–588 (2021).
  Article CAS PubMed PubMed Central Google Scholar
• Garbern, J. C. & Lee, R. T. Heart regeneration: 20 years of progress and renewed optimism. Dev. Cell 57, 424–439 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Vujic, A., Natarajan, N. & Lee, R. T. Molecular mechanisms of heart regeneration. Semin. Cell Dev. Biol. 100, 20–28 (2020).
  Article CAS PubMed Google Scholar
• Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Gourdie, R. G., Dimmeler, S. & Kohl, P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat. Rev. Drug Discov. 15, 620–638 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• van den Borne, S. W. M. et al. Myocardial remodeling after infarction: the role of myofibroblasts. Nat. Rev. Cardiol. 7, 30–37 (2010).
  Article PubMed Google Scholar
• Roche, P. L., Filomeno, K. L., Bagchi, R. A. & Czubryt, M. P. Intracellular signaling of cardiac fibroblasts. in Comprehensive Physiology 721–760. https://doi.org/10.1002/cphy.c140044 (Wiley, 2015).
• Grotendorst, G. R. & Duncan, M. R. Individual domains of connective tissue growth factor regulate fibroblast proliferation and myofibroblast differentiation. FASEB J. 19, 729–738 (2005).
  Article CAS PubMed Google Scholar
• Aghajanian, H. et al. Targeting cardiac fibrosis with engineered T cells. Nature 573, 430–433 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Maisel, A. S. & Choudhary, R. Biomarkers in acute heart failure—state of the art. Nat. Rev. Cardiol. 9, 478–490 (2012).
  Article CAS PubMed Google Scholar
• Ahmad, T., Fiuzat, M., Felker, G. M. & O’Connor, C. Novel biomarkers in chronic heart failure. Nat. Rev. Cardiol. 9, 347–359 (2012).
  Article CAS PubMed Google Scholar
• Chirinos, J. A. et al. Endotrophin, a collagen VI formation-derived peptide, in heart failure. NEJM Evid. 1, EVIDoa2200091 (2022).
• Lederer, D. J. & Martinez, F. J. Idiopathic pulmonary fibrosis. N. Engl. J. Med. 378, 1811–1823 (2018).
  Article CAS PubMed Google Scholar
• Chambers, R. C. & Mercer, P. F. Mechanisms of alveolar epithelial injury, repair, and fibrosis. Ann. Am. Thorac. Soc. 12, S16–S20 (2015).
  Article PubMed PubMed Central Google Scholar
• Xu, J. et al. Use of senescence-accelerated mouse model in bleomycin-induced lung injury suggests that bone marrow-derived cells can alter the outcome of lung injury in aged mice. J. Gerontol. A Biol. Sci. Med. Sci. 64 A, 731–739 (2009).
  Article Google Scholar
• Kathiriya, J. J. et al. Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells. Nat. Cell Biol. 24, 10–23 (2022).
  Article CAS PubMed Google Scholar
• Melo-Narváez, M. C., Stegmayr, J., Wagner, D. E. & Lehmann, M. Lung regeneration: implications of the diseased niche and ageing. Eur. Respir. Rev. 29, 200222 (2020).
  Article PubMed PubMed Central Google Scholar
• Wu, H. et al. Progressive pulmonary fibrosis is caused by elevated mechanical tension on alveolar stem. Cells Cell 180, 107–121.e17 (2020).
  Article CAS PubMed Google Scholar
• Knüppel, L. et al. A novel antifibrotic mechanism of nintedanib and pirfenidone. inhibition of collagen fibril assembly. Am. J. Respir. Cell Mol. Biol. 57, 77–90 (2017).
  Article PubMed Google Scholar
• Finnerty, J. P., Ponnuswamy, A., Dutta, P., Abdelaziz, A. & Kamil, H. Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both idiopathic pulmonary fibrosis (IPF) and non-IPF: a systematic review and meta-analysis. BMC Pulm. Med. 21, 411 (2021).
• Wind, S. et al. Clinical pharmacokinetics and pharmacodynamics of nintedanib. Clin. Pharmacokinet. 58, 1131–1147 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Flaherty, K. R. et al. Nintedanib in progressive fibrosing interstitial lung diseases. N. Engl. J. Med. 381, 1718–1727 (2019).
  Article CAS PubMed Google Scholar
• Bhatt, S. P. et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N. Engl. J. Med. 389, 205–214 (2023).
  Article CAS PubMed Google Scholar
• Bhatt, S. P. et al. Dupilumab for COPD with blood eosinophil evidence of type 2 inflammation. N. Engl. J. Med. 390, 2274–2283 (2024).
  Article CAS PubMed Google Scholar
• Balzer, M. S. et al. Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration. Nat. Commun. 13, 4018 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Doke, T. et al. Single-cell analysis identifies the interaction of altered renal tubules with basophils orchestrating kidney fibrosis. Nat. Immunol. 23, 947–959 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Fioretto, P., Steffes, M. W., Sutherland, D. E. R., Goetz, F. C. & Mauer, M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N. Engl. J. Med. 339, 69–75 (1998).
  Article CAS PubMed Google Scholar
• Tajima, K. et al. An organ-derived extracellular matrix triggers in situ kidney regeneration in a preclinical model. NPJ Regen. Med. 7, 18 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Ruiz-Ortega, M., Rayego-Mateos, S., Lamas, S., Ortiz, A. & Rodrigues-Diez, R. R. Targeting the progression of chronic kidney disease. Nat. Rev. Nephrol. 16, 269–288 (2020).
  Article PubMed Google Scholar
• Perkovic, V. et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N. Engl. J. Med. 391, 109–121 (2024).
  Article CAS PubMed Google Scholar
• Greenberg, J. H. et al. Urine biomarkers of kidney tubule health, injury, and inflammation are associated with progression of CKD in children. J. Am. Soc. Nephrol. 32, 2664–2677 (2021).
  Article CAS PubMed PubMed Central Google Scholar
• Sparding, N. et al. Unique biomarkers of collagen type III remodeling reflect different information regarding pathological kidney tissue alterations in patients with IgA nephropathy. Biomolecules 13, 1093 (2023).
• Zhang, X.-Q. et al. Serum lysyl oxidase is a potential diagnostic biomarker for kidney fibrosis. Am. J. Nephrol. 51, 907–918 (2020).
  Article CAS PubMed Google Scholar
• Zewinger, S. et al. Dickkopf-3 (DKK3) in urine identifies patients with short-term risk of eGFR loss. J. Am. Soc. Nephrol. 29, 2722–2733 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Genovese, F. et al. Collagen type III and VI remodeling biomarkers are associated with kidney fibrosis in lupus nephritis. Kidney360 2, 1473–1481 (2021).
  Article PubMed PubMed Central Google Scholar
• Sparding, N. et al. Circulating levels of endotrophin are prognostic for long-term mortality after AKI. Kidney360 3, 809–817 (2022).
  Article PubMed PubMed Central Google Scholar
• D’Alessio, S. et al. Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat. Rev. Gastroenterol. Hepatol. 19, 169–184 (2022).
  Article PubMed Google Scholar
• Domislović, V. et al. Differences in extra cellular matrix remodelling in highly active Crohn’s disease and ulcerative colitis. J. Crohns Colitis 14, S156–S157 (2020).
  Article Google Scholar
• Mortensen, J. H. et al. The intestinal tissue homeostasis–the role of extracellular matrix remodeling in inflammatory bowel disease. Expert Rev. Gastroenterol. Hepatol. 13, 977–993 (2019).
• van Haaften, W. T. et al. Misbalance in type III collagen formation/degradation as a novel serological biomarker for penetrating (Montreal B3) Crohn’s disease. Aliment Pharm. Ther. 46, 26–39 (2017).
  Article Google Scholar
• Mortensen, J. H. et al. Fragments of citrullinated and MMP-degraded vimentin and MMP-degraded type III collagen are novel serological biomarkers to differentiate Crohn’s disease from ulcerative colitis. J. Crohns Colitis 9, 863–872 (2015).
  Article PubMed Google Scholar
• Bourgonje, A. R. et al. Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohnʼs disease. Aliment. Pharmacol. Ther. 1–19. https://doi.org/10.1111/apt.17063 (2022).
• Alexdottir, M. S. et al. Serological biomarkers of extracellular matrix turnover and neutrophil activity are associated with long-term use of vedolizumab in patients with Crohn’s disease. Int J. Mol. Sci. 23, i468–i469 (2022).
  Article Google Scholar
• van Haaften, W. T. et al. Serological biomarkers of tissue turnover identify responders to anti-TNF therapy in Crohn’s disease: a pilot study. Clin. Transl. Gastroenterol. 11, e00217 (2020).
• Mortensen, J. H. et al. The citrullinated and MMP-degraded vimentin biomarker (VICM) predicts early response to anti-TNFα treatment in Crohn’s disease. J. Clin. Gastroenterol. 55, 59–66 (2021).
  Article CAS PubMed Google Scholar
• Alexdottir, M. S. et al. Serological biomarkers of intestinal collagen turnover identify early response to infliximab therapy in patients with Crohn’ s disease. Int. J. Mol. Sci. 23, 8137 (2022).
• Manon-Jensen, T. et al. Elevated ectodomain of type 23 collagen is a novel biomarker of the intestinal epithelium to monitor disease activity in ulcerative colitis and Crohn’s disease. United Eur. Gastroenterol. J. https://doi.org/10.1177/2050640620977371 (2020).
• Jensen, C. et al. Serum type XVI collagen is associated with colorectal cancer and ulcerative colitis indicating a pathological role in gastrointestinal disorders. Cancer Med. 1–8. https://doi.org/10.1002/cam4.1692 (2018).
• Sun, S. et al. Serological assessment of the quality of wound healing processes in Crohn’s disease. J. Gastrointest. Liver Dis. 28, 175–182 (2019).
  Article CAS Google Scholar
• Pehrsson, M., Alexdóttir, M. S., Karsdal, M. A., Thakker, P. & Mortensen, J. H. Novel fibro-inflammatory biomarkers associated with disease activity in patients with Crohn’s disease. Expert Rev. Gastroenterol. Hepatol. 00, 1–13 (2023).
  Google Scholar
• Yoo, J. H., Holubar, S. & Rieder, F. Fibrostenotic strictures in Crohn’s disease. Intest Res 18, 379–401 (2020).
  Article PubMed PubMed Central Google Scholar
• De Bruyn, J. R. et al. Development of fibrosis in acute and longstanding ulcerative colitis. J. Crohns Colitis 9, 966–972 (2015).
  Article PubMed Google Scholar
• Gordon, I. O. et al. Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation. Aliment. Pharm. Ther. 47, 922–939 (2018).
  Article CAS Google Scholar
• De Bruyn, J. R. et al. Intestinal fibrosis is associated with lack of response to infliximab therapy in Crohn’s disease. PLoS ONE 13, 1–13 (2018).
  Article Google Scholar
• Lawrance, I. C. et al. Cellular and molecular mediators of intestinal fibrosis. J. Crohns Colitis j.crohns.2014.09.008, https://doi.org/10.1016/j.crohns.2014.09.008 (2015).
• Neurath, M. F. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat. Immunol. 20, 970–979 (2019).
  Article CAS PubMed Google Scholar
• Stolfi, C., Troncone, E., Marafini, I. & Monteleone, G. Role of TGF-beta and Smad7 in gut inflammation, fibrosis and cancer. Biomolecules 11, 17 (2020).
  Article PubMed PubMed Central Google Scholar
• Gundersen, M. D. et al. Fibrosis mediators in the colonic mucosa of acute and healed ulcerative colitis. Clin. Transl. Gastroenterol. 10, e00082 (2019).
  Article PubMed PubMed Central Google Scholar
• Rieder, F., Brenmoehl, J., Leeb, S., Scholmerich, J. & Rogler, G. Wound healing and fibrosis in intestinal disease. Gut 56, 130–139 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Hamilton, A. L. et al. Serologic antibodies in relation to outcome in postoperative Crohn’s disease. J. Gastroenterol. Hepatol. 32, 1195–1203 (2017).
  Article CAS PubMed Google Scholar
• Zhao, Z., Cheng, W., Qu, W., Shao, G. & Liu, S. Antibiotic alleviates radiation-induced intestinal injury by remodeling microbiota, reducing inflammation, and inhibiting fibrosis. ACS Omega 5, 2967–2977 (2020).
  Article CAS PubMed PubMed Central Google Scholar
• Ellermann, M. et al. Yersiniabactin-producing adherent/invasive escherichia coli promotes inflammation-associated fibrosis in gnotobiotic Il10 −/− Mice. Infect. Immun. 87, e00587-19 (2019).
• Mortensen, J. H. et al. A specific calprotectin neo-epitope [CPa9-HNE] in serum from inflammatory bowel disease patients is associated with neutrophil activity and endoscopic severity. J. Crohns Colitis 1–14. https://doi.org/10.1093/ecco-jcc/jjac047 (2022).
• Chrysanthopoulou, A. et al. Neutrophil extracellular traps promote differentiation and function of fibroblasts. J. Pathol. 233, 294–307 (2014).
  Article CAS PubMed Google Scholar
• Chokr, D. et al. Adherent invasive Escherichia coli (AIEC) strain LF82, but not Candida albicans, plays a profibrogenic role in the intestine. Gut Pathog. 13, 5 (2021).
  Article CAS PubMed PubMed Central Google Scholar
• O’Donnell, S., O’Sullivan, M., O’Morain, C. A. & Ryan, B. M. The clinical significance of antimicrobial serologic responses within an Irish Crohn’s disease population. Eur. J. Gastroenterol. Hepatol. 25, 1464–1469 (2013).
  Article PubMed Google Scholar
• Dubinsky, M. C. et al. Serum immune responses predict rapid disease progression among children with Crohn’s disease: immune responses predict disease progression. Am. J. Gastroenterol. 101, 360–367 (2006).
  Article PubMed PubMed Central Google Scholar
• Park, J.-S. et al. Lactobacillus acidophilus improves intestinal inflammation in an acute colitis mouse model by regulation of Th17 and treg cell balance and fibrosis development. J. Med Food 21, 215–224 (2018).
  Article CAS PubMed Google Scholar
• Braat, H. et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin. Gastroenterol. Hepatol. 4, 754–759 (2006).
  Article CAS PubMed Google Scholar
• Zheng, J. et al. Noninvasive, microbiome-based diagnosis of inflammatory bowel disease. Nat. Med 30, 3555–3567 (2024).
  Article CAS PubMed PubMed Central Google Scholar
• Sandborn, W. J. et al. Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn’s disease. Gastroenterology 158, 2123–2138.e8 (2020).
  Article CAS PubMed Google Scholar
• Roblin, X. et al. Effects of JAK1-preferential inhibitor filgotinib on circulating biomarkers and whole blood genes/pathways of patients with moderately to severely active Crohn’s disease. Inflamm. Bowel Dis. 28, 1207–1218 (2022).
  Article PubMed Google Scholar
• Wang, J. et al. Preventing fibrosis in IBD: update on immune pathways and clinical strategies. Expert Rev. Clin. Immunol. 20, 727–734 (2024).
  Article CAS PubMed Google Scholar
• Sakers, A., De Siqueira, M. K., Seale, P. & Villanueva, C. J. Adipose-tissue plasticity in health and disease. Cell 185, 419–446 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Bonfante, I. L. P. et al. Combined training increases thermogenic fat activity in patients with overweight and type 2 diabetes. Int J. Obes. 46, 1145–1154 (2022).
  Article CAS Google Scholar
• Finlin, B. S. et al. Adipose tissue mast cells promote human adipose beiging in response to cold. Sci. Rep. 9, 8658 (2019).
  Article PubMed PubMed Central Google Scholar
• Funcke, J.-B. & Scherer, P. E. Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J. Lipid Res 60, 1648–1697 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Meyer, L. K., Ciaraldi, T. P., Henry, R. R., Wittgrove, A. C. & Phillips, S. A. Adipose tissue depot and cell size dependency of adiponectin synthesis and secretion in human obesity. Adipocyte 2, 217–226 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Van Heek, M. et al. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J. Clin. Investig. 99, 385–390 (1997).
  Article PubMed PubMed Central Google Scholar
• Kelley, D. E., Thaete, F. L., Troost, F., Huwe, T. & Goodpaster, B. H. Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 278, E941–E948 (2000).
  Article CAS PubMed Google Scholar
• Vishvanath, L. & Gupta, R. K. Contribution of adipogenesis to healthy adipose tissue expansion in obesity. J. Clin. Investig. 129, 4022–4031 (2019).
  Article PubMed PubMed Central Google Scholar
• Sun, K., Tordjman, J., Clément, K. & Scherer, P. E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Henriksen, K. et al. Endotrophin, a key marker and driver for fibroinflammatory disease. Endocr. Rev. 45, 361–378 (2024).
  Article PubMed Google Scholar
• Zhu, Q. & Scherer, P. E. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat. Rev. Nephrol. 14, 105–120 (2018).
  Article CAS PubMed Google Scholar
• Ma, L.-J. et al. Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity. Am. J. Physiol. Ren. Physiol. 300, F1203–F1213 (2011).
  Article CAS Google Scholar
• Griendling, K. K., Minieri, C. A., Ollerenshaw, J. D. & Alexander, R. W. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ. Res. 74, 1141–1148 (1994).
  Article CAS PubMed Google Scholar
• Lim, C. C. et al. Elevated serum leptin, adiponectin and leptin to adiponectin ratio is associated with chronic kidney disease in Asian adults. PLoS ONE 10, e0122009 (2015).
  Article PubMed PubMed Central Google Scholar
• Wolf, G. et al. Leptin stimulates proliferation and TGF-β expression in renal glomerular endothelial cells: potential role in glomerulosclerosis. Kidney Int 56, 860–872 (1999).
  Article CAS PubMed Google Scholar
• Cui, W., Maimaitiyiming, H., Qi, X., Norman, H. & Wang, S. Thrombospondin 1 mediates renal dysfunction in a mouse model of high-fat diet-induced obesity. Am. J. Physiol.-Ren. Physiol. 305, F871–F880 (2013).
  Article CAS Google Scholar
• Mao, R. et al. The mesenteric fat and intestinal muscle interface: creeping fat influencing stricture formation in Crohn’s disease. Inflamm. Bowel Dis. 25, 421–426 (2019).
  Article PubMed Google Scholar
• HALPRIN, K. M. Epidermal ‘turnover time’–a re-examination. Br. J. Dermatol 86, 14–19 (1972).
  Article CAS PubMed Google Scholar
• Lorenz, H. P. et al. Scarless wound repair: a human fetal skin model. Development 114, 253–259 (1992).
  Article CAS PubMed Google Scholar
• Watt, F. M. The stem cell compartment in human interfollicular epidermis. J. Dermatol. Sci. 28, 173–180 (2002).
  Article CAS PubMed Google Scholar
• Gomes, M. L. N. P., Krijnen, P. A. J., Middelkoop, E., Niessen, H. W. M. & Boekema, B. K. H. L. Fetal skin wound healing: key extracellular matrix components and regulators in scarless healing. J. Investig. Dermatol. https://doi.org/10.1016/J.JID.2024.05.027 (2024).
• Canady, J., Karrer, S., Fleck, M. & Bosserhoff, A. K. Fibrosing connective tissue disorders of the skin: molecular similarities and distinctions. J. Dermatol Sci. 70, 151–158 (2013).
  Article CAS PubMed Google Scholar
• Bailey, J., Schwehr, M. & Beattie, A. Management of keloids and hypertrophic scars. Am. Fam. Physician 110, 605–611 (2024).
  PubMed Google Scholar
• Wang, Q., Ren, Z., Jin, W. & Jin, Z. Real-world effectiveness and safety of bleomycin in patients with keloids and hypertrophic scars: a systematic review and meta-analysis. Arch. Dermatol. Res. 317, 170 (2025).
• Pérez, L. A., Leyton, L. & Valdivia, A. Thy-1 (CD90), Integrins and syndecan 4 are key regulators of skin wound healing. Front. Cell Dev. Biol. 10, https://doi.org/10.3389/fcell.2022.810474 (2022).
• Hayn, E. Successful treatment of complex traumatic and surgical wounds with a foetal bovine dermal matrix. Int. Wound J. 11, 675–680 (2014).
  Article PubMed Google Scholar
• Dobrota, R. et al. Circulating collagen neo-epitopes and their role in the prediction of fibrosis in patients with systemic sclerosis: a multicentre cohort study. Lancet Rheumatol. 3, e175–e184 (2021).
  Article CAS PubMed Google Scholar
• Tomcik, M. et al. S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis. Ann. Rheum. Dis. 74, 1748–1755 (2015).
  Article CAS PubMed Google Scholar
• Leask, A., Naik, A. & Stratton, R. J. Back to the future: targeting the extracellular matrix to treat systemic sclerosis. Nat. Rev. Rheumatol. 19, 713–723 (2023).
  Article PubMed Google Scholar
• Steen, V. D. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 35, 35–42 (2005).
  Article CAS PubMed Google Scholar
• Graf, S. W. et al. South Australian Scleroderma Register: autoantibodies as predictive biomarkers of phenotype and outcome. Int. J. Rheum. Dis. 15, 102–109 (2012).
  Article PubMed Google Scholar
• Walker, J. G. & Fritzler, M. J. Update on autoantibodies in systemic sclerosis. Curr. Opin. Rheumatol. 19, 580–591 (2007).
  Article PubMed Google Scholar
• Walker, U. A. et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann. Rheum. Dis. 66, 754–763 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Reveille, J. D. et al. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum. 49, 399–412 (2003).
  Article PubMed Google Scholar
• Steen, V. D., Powell, D. L. & Medsger, T. A. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum. 31, 196–203 (1988).
  Article CAS PubMed Google Scholar
• Hesselstrand, R., Scheja, A., Shen, G. Q., Wiik, A. & Åkesson, A. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatol. (Oxf.) 42, 534–540 (2003).
  Article CAS Google Scholar
• Hanke, K. et al. Diagnostic value of anti-topoisomerase I antibodies in a large monocentric cohort.Arthritis Res. Ther. 11, R28 (2009).
  Article PubMed PubMed Central Google Scholar
• Abignano, G. et al. The enhanced liver fibrosis test: a clinical grade, validated serum test, biomarker of overall fibrosis in systemic sclerosis. Ann. Rheum. Dis. 73, 420–427 (2014).
  Article PubMed Google Scholar
• Jurisic, Z. et al. Relationship between interleukin-6 and cardiac involvement in systemic sclerosis. Rheumatology 52, 1296–1302 (2013).
  Article Google Scholar
• Codullo, V. et al. An investigation of the inflammatory cytokine and chemokine network in systemic sclerosis. Ann. Rheum. Dis. 70, 1115–1121 (2011).
  Article CAS PubMed Google Scholar
• Puccetti, A. & Migliorini, P. Human and murine anti-DNA antibodies induce the production of anti-idiotypic antibodies with autoantigen-binding properties (epibodies) through immune-network interactions. J. Immunol. 15, 4229–4237 (1990).
  Article Google Scholar
• Khanna, D. et al. A 24-week, phase iia, randomized, double-blind, placebo-controlled study of ziritaxestat in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 75, 1434–1444 (2023).
  Article CAS PubMed Google Scholar
• Sheng, X. R. et al. Biomarkers of fibrosis, inflammation, and extracellular matrix in the phase 3 trial of tocilizumab in systemic sclerosis. Clin. Immunol. 254, 109695 (2023).
  Article CAS PubMed Google Scholar
• Baka, J. L. Ce. S. et al. Stiff skin syndrome: long-term follow-up. Bras. Dermatol 99, 597 (2024).
  Article Google Scholar
• Fusco, C. et al. Pro-fibrotic phenotype in a patient with segmental stiff skin syndrome via TGF-β signaling overactivation. Int J. Mol. Sci. 21, 5141 (2020).
  Article CAS PubMed PubMed Central Google Scholar
• Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411–428 (2019).
  Article PubMed Google Scholar
• Gofton, C., Upendran, Y., Zheng, M.-H. & George, J. MAFLD: how is it different from NAFLD? Clin. Mol. Hepatol. 29, S17–S31 (2023).
  Article PubMed Google Scholar
• Sanyal, A. J. et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N. Engl. J. Med. 385, 1559–1569 (2021).
  Article CAS PubMed PubMed Central Google Scholar
• Konyn, P., Ahmed, A. & Kim, D. Causes and risk profiles of mortality among individuals with nonalcoholic fatty liver disease. Clin. Mol. Hepatol. 29, S43–S57 (2023).
  Article PubMed Google Scholar
• Cypess, A. M. Reassessing human adipose tissue. N. Engl. J. Med. 386, 768–779 (2022).
  Article CAS PubMed Google Scholar
• Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).
  Article PubMed PubMed Central Google Scholar
• Nagai, A. et al. Overview of the BioBank Japan Project: study design and profile. J. Epidemiol. 27, S2–S8 (2017).
  Article PubMed PubMed Central Google Scholar
• Hardy, T. et al. The European NAFLD Registry: a real-world longitudinal cohort study of nonalcoholic fatty liver disease. Contemp. Clin. Trials 98, 106175 (2020).
  Article PubMed Google Scholar
• Wilhelm, M. et al. Mass-spectrometry-based draft of the human proteome. Nature 509, 582–587 (2014).
  Article CAS PubMed Google Scholar
• Kim, M.-S. et al. A draft map of the human proteome. Nature 509, 575–581 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Oh, H. S.-H. et al. Organ aging signatures in the plasma proteome track health and disease. Nature 624, 164–172 (2023).
  Article CAS PubMed PubMed Central Google Scholar
• Niu, L. et al. Noninvasive proteomic biomarkers for alcohol-related liver disease. Nat. Med. 28, 1277–1287 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Govaere, O. et al. A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures. Nat. Metab. 5, 572–578 (2023).
  Article CAS PubMed PubMed Central Google Scholar
• Eldjarn, G. H. et al. Large-scale plasma proteomics comparisons through genetics and disease associations. Nature 622, 348–358 (2023).
  Article CAS PubMed PubMed Central Google Scholar
• Schuppan, D., Myneni, S. & Surabattula, R. Liquid biomarkers for fibrotic NASH—progress in a complex field. J. Hepatol. 76, 5–7 (2022).
  Article PubMed Google Scholar
• Huan, T. et al. Integrative analysis of clinical and epigenetic biomarkers of mortality.Aging Cell 21, e13608 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Deelen, J. et al. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals. Nat. Commun. 10, 3346 (2019).
  Article PubMed PubMed Central Google Scholar
• Jørgensen, J. T. The current landscape of the FDA approved companion diagnostics. Transl. Oncol. 14, 101063 (2021).
  Article PubMed PubMed Central Google Scholar
• Nielsen, M. J. et al. The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. Am. J. Transl. Res. 5, 303–315 (2013).
  CAS PubMed PubMed Central Google Scholar
• Jansen, C. et al. PRO-C3-levels in patients with HIV/HCV-Co-infection reflect fibrosis stage and degree of portal hypertension. PLoS ONE 9, e108544 (2014).
  Article PubMed PubMed Central Google Scholar
• Genovese, F. et al. Plasma levels of PRO-C3, a type III collagen synthesis marker, are associated with arterial stiffness and increased risk of cardiovascular death. Atherosclerosis 388, 117420 (2024).
  Article CAS PubMed Google Scholar
• Nielsen, M. J. et al. Serological markers of extracellular matrix remodeling predict transplant-free survival in primary sclerosing cholangitis. Aliment Pharm. Ther. 48, 179–189 (2018).
  Article CAS Google Scholar
• Lichtinghagen, R. et al. The enhanced liver fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J. Hepatol. 59, 236–242 (2013).
  Article PubMed Google Scholar
• Parkes, J. et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut 59, 1245–1251 (2010).
  Article CAS PubMed Google Scholar
• Mayo, M. J. et al. Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology 48, 1549–1557 (2008).
  Article PubMed Google Scholar
• Sun, K., Park, J., Kim, M. & Scherer, P. E. Endotrophin, a multifaceted player in metabolic dysregulation and cancer progression, is a predictive biomarker for the response to PPARγ agonist treatment. Diabetologia 60, 24–29 (2017).
  Article CAS PubMed Google Scholar
• Luther, D. J. et al. Absence of type VI collagen paradoxically improves cardiac function, structure, and remodeling after myocardial infarction. Circ. Res 110, 851–856 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Lin, S.-N. et al. Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells – A novel mechanism for maintenance of intestinal inflammation. Matrix Biol. 113, 1–21 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Stolz, D. et al. Systemic biomarkers of collagen and elastin turnover are associated with clinically relevant outcomes in COPD. Chest 151, 47–59 (2017).
  Article PubMed Google Scholar
• Rønnow, S. R. et al. Endotrophin, an extracellular hormone, in combination with neoepitope markers of von Willebrand factor improves prediction of mortality in the ECLIPSE COPD cohort. Respir. Res. 21, 202 (2020).
  Article PubMed PubMed Central Google Scholar
• Kerbert, A. J. C. et al. Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure. JHEP Rep. 3, 100355 (2021).
  Article PubMed PubMed Central Google Scholar
• Sparding, N. et al. Endotrophin levels are associated with allograft outcomes in kidney transplant recipients. Biomolecules 13, 792 (2023).
  Article CAS PubMed PubMed Central Google Scholar
• Nissen, N. I. et al. Prognostic value of blood-based fibrosis biomarkers in patients with metastatic colorectal cancer receiving chemotherapy and bevacizumab. Sci. Rep. 11, 865 (2021).
  Article CAS PubMed PubMed Central Google Scholar
• Nissen, N. I. et al. Collagen biomarkers quantify fibroblast activity in vitro and predict survival in patients with pancreatic ductal adenocarcinoma. Cancers 14, 819 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• Leeming, D. J. et al. Endotrophin, a pro-peptide of Type VI collagen, is a biomarker of survival in cirrhotic patients with hepatocellular carcinoma. Hepat. Oncol. 8, HEP32 (2021).
  Article Google Scholar
• Pilemann-Lyberg, S. et al. Markers of collagen formation and degradation reflect renal function and predict adverse outcomes in patients with type 1 diabetes. Diab. Care 42, 1760–1768 (2019).
  Article CAS Google Scholar
• Rasmussen, D. G. K. et al. Higher collagen VI formation is associated with all-cause mortality in patients with type 2 diabetes and microalbuminuria. Diab. Care 41, 1493–1500 (2018).
  Article CAS Google Scholar
• Tougaard, N. H. et al. Endotrophin as a marker of complications in a type 2 diabetes cohort. Diab. Care 45, 2746–2748 (2022).
  Article CAS Google Scholar
• Genovese, F. et al. The fibroblast hormone endotrophin is a biomarker of mortality in chronic diseases. Matrix Biol. https://doi.org/10.1016/j.matbio.2024.06.003 (2024).
• 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).
  Article PubMed Google Scholar
• Kingwell, K. NASH field celebrates ‘hurrah moment’ with a first FDA drug approval for the liver disease. Nat. Rev. Drug Discov. https://doi.org/10.1038/d41573-024-00051-1 (2024).
• Friedman, S. L., Sheppard, D., Duffield, J. S. & Violette, S. Therapy for fibrotic diseases: nearing the starting line. Sci. Transl. Med. 5, 167sr1 (2013).
  Article PubMed Google Scholar
• Schuppan, D. & Kim, Y. O. Evolving therapies for liver fibrosis. J. Clin. Investig. 123, 1887–1901 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Bay-Jensen, A. C. et al. Ankylosing spondylitis is characterized by an increased turnover of several different metalloproteinase-derived collagen species: a cross-sectional study. Rheumatol. Int. 32, 3565–3572 (2012).
  Article CAS PubMed Google Scholar
• Willumsen, N. et al. Extracellular matrix specific protein fingerprints measured in serum can separate pancreatic cancer patients from healthy controls. BMC Cancer 13, 554 (2013).
  Article PubMed PubMed Central Google Scholar
• Dooling, L. J., Saini, K., Anlaş, A. A. & Discher, D. E. Tissue mechanics coevolves with fibrillar matrisomes in healthy and fibrotic tissues. Matrix Biol. 111, 153–188 (2022).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Rasmussen, D. G. K. et al. NAFLD and NASH biomarker qualification in the LITMUS consortium—lessons learned. J. Hepatol. 78, 852–865 (2023).
  Article CAS PubMed Google Scholar