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We previously showed that heparin\u2013polyethylene glycol (PEG) hydrogels loaded with transforming growth factor TGF-\u03b2 instructed stable chondral MSC development in\u00a0vivo. Here, we assessed this approach in\u00a0vitro, utilizing heparin\u2013PEG hydrogels or the pellet culture system with soluble heparin supplementation of chondrogenic medium.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human MSCs were cultured in heparin\u2013PEG hydrogels (22.4\u00a0mg\/mL crosslinked heparin, 120\u00a0ng TGF-\u03b21) or as pellet cultures treated with soluble heparin (0, 10, 100, 700\u00a0\u03bcg\/mL) in TGF-\u03b21-containing (10\u00a0ng\/mL) chondrogenic medium. Chondral and endochondral signaling (1\u20133\u00a0h, 4\u00a0weeks) and cartilage matrix formation (4\u00a0weeks) were analyzed using western blot, histology, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and enzyme activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Unlike in\u00a0vivo, human MSCs differentiated in heparin\u2013PEG hydrogels into type X collagen and alkaline phosphatase-positive hypertrophic chondrocytes in\u00a0vitro. Interestingly, treating MSC pellets with soluble heparin (10\u2013700\u00a0\u00b5g\/mL) revealed reduced TGF-\u03b2-SMAD3 but not SMAD2 activation at unaffected type II collagen and proteoglycan\/DNA levels. We propose that the stimulation of the insulin-AKT pathway by heparin aided in maintaining SMAD2 activation, which apparently plays a more prominent role than SMAD3 for MSC chondrogenesis. Heparin treatment inhibited the pro-hypertrophic WNT\/\u03b2-catenin pathway in\u00a0vitro but insufficiently silenced TGF-\u03b2-SMAD1\/5\/9 activation and unfortunately reduced antihypertrophic prostaglandin PGE2 levels. Ultimately, treatment with 10\u00a0\u00b5g\/mL heparin reduced the upregulation of several hypertrophy markers (\n                      <jats:italic>MEF2C<\/jats:italic>\n                      ,\n                      <jats:italic>IHH<\/jats:italic>\n                      ,\n                      <jats:italic>IBSP<\/jats:italic>\n                      messenger RNAs [mRNAs], alkaline phosphatase activity) below control levels, but type X collagen remained unresponsive. Thus, soluble heparin treatment was similarly selective and effective as previous antihypertrophic interventions (PTHrP pulses, WNT inhibition), while offering technical simplicity, reduced cost, and solvent-free formulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Taken together, heparin-TGF-\u03b2 showed a novel dichotomous SMAD2\/3 inhibition at maintained chondrogenic differentiation and context-dependent lineage-instructive properties\u2014permitting endochondral commitment in\u00a0vitro but chondral development in\u00a0vivo. Thus, environmental contributions are mandatory to allow heparin\u2013PEG-guided chondral versus endochondral lineage commitment of MSCs in\u00a0vivo, potentially involving SMAD1\/5\/9 suppressors and PGE2 sources.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s11658-026-00899-8","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T18:51:15Z","timestamp":1773773475000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dichotomous SMAD2\/3 regulation and selective antihypertrophic activity of heparin during in\u00a0vitro chondrogenesis of mesenchymal stromal cells"],"prefix":"10.1186","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0558-4001","authenticated-orcid":false,"given":"Sven","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7558-6032","authenticated-orcid":false,"given":"Safak","family":"Chasan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8409-3221","authenticated-orcid":false,"given":"Helen F.","family":"Dietmar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2684-6890","authenticated-orcid":false,"given":"Felicia A. 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Human MSCs were isolated from bone marrow samples after obtaining written informed consent by the patients.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors approved the final manuscript to be published.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"During the preparation of this work, the authors used YoKI (meta-llama\/Meta-Llama-3.1-70B) to assist with language editing and Perplexity (\n                      \n                      ) for literature research. After using these tools, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declaration of AI and AI-assisted technologies in the writing process"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"51"}}