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Our study aimed to investigate the effects of TGF-\u03b21 and TGF-\u03b23 on myofibroblast differentiation and extracellular matrix deposition in different types of fibroblasts, including normal\/dermal, cancer-associated, and scar-derived fibroblasts. When comparing the phenotype and signaling pathways activation we observed extreme heterogeneity of studied markers across different fibroblast populations, even within those isolated from the same tissue. Specifically, the presence of myofibroblast and deposition of extracellular matrix were dependent on the origin of the fibroblasts and the type of treatment they received (TGF-\u03b21 vs. TGF-\u03b23). In parallel, we detected activation of canonical signaling (pSMAD2\/3) across all studied fibroblasts, albeit to various extents. Treatment with TGF-\u03b21 and TGF-\u03b23 resulted in the activation of canonical and several non-canonical pathways, including AKT, ERK, and ROCK. Among studied cells, cancer-associated fibroblasts displayed the most heterogenic response to TGF-\u03b21\/3 treatments. In general, TGF-\u03b21 demonstrated a more potent activation of signaling pathways compared to TGF-\u03b23, whereas TGF-\u03b23 exhibited rather an inhibitory effect in keloid- and hypertrophic scar-derived fibroblasts suggesting its clinical potential for scar treatment. In summary, our study has implications for comprehending the role of TGF-\u03b2 signaling in fibroblast biology, fibrotic diseases, and cancer. Future research should focus on unraveling the mechanisms beyond differential fibroblast responses to TGF-\u03b2 isomers considering inherent fibroblast heterogeneity.<\/jats:p>","DOI":"10.1007\/s00418-023-02221-5","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T14:57:13Z","timestamp":1694703433000},"page":"541-554","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Heterogeneous response to TGF-\u03b21\/3 isoforms in fibroblasts of different origins: implications for wound healing and tumorigenesis"],"prefix":"10.1007","volume":"160","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2769-4295","authenticated-orcid":false,"given":"Luk\u00e1\u0161","family":"Urban","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4450-2083","authenticated-orcid":false,"given":"Mat\u00fa\u0161","family":"\u010coma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1750-9933","authenticated-orcid":false,"given":"Luk\u00e1\u0161","family":"Lacina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1944-1493","authenticated-orcid":false,"given":"Pavol","family":"Szabo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2821-8150","authenticated-orcid":false,"given":"Jana","family":"Sabov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5061-0585","authenticated-orcid":false,"given":"Tom\u00e1\u0161","family":"Urban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5655-5572","authenticated-orcid":false,"given":"Hubert","family":"\u0160uca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5922-5958","authenticated-orcid":false,"given":"\u0160tefan","family":"Luka\u010d\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7372-5315","authenticated-orcid":false,"given":"Robert","family":"Zaj\u00ed\u010dek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7878-8403","authenticated-orcid":false,"suffix":"Jr","given":"Karel","family":"Smetana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3398-3408","authenticated-orcid":false,"given":"Peter","family":"G\u00e1l","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"2221_CR1","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1038\/ncomms1734","volume":"3","author":"A Akhmetshina","year":"2012","unstructured":"Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, Schneider H, Sadowski A, Riener MO, MacDougald OA, Distler O, Schett G, Distler JH (2012) Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. 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