{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T10:54:16Z","timestamp":1784112856346,"version":"3.55.0"},"reference-count":66,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007557","name":"CIRM","doi-asserted-by":"publisher","award":["TR1-01216"],"award-info":[{"award-number":["TR1-01216"]}],"id":[{"id":"10.13039\/100007557","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007557","name":"CIRM","doi-asserted-by":"publisher","award":["PC1-08128"],"award-info":[{"award-number":["PC1-08128"]}],"id":[{"id":"10.13039\/100007557","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Donald and Darlene Shiley"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mesenchymal stem cells (MSCs) exert biological effects in part through their secretome which includes extracellular vesicles. In this study, we isolated and characterized the secretome from clinically relevant stem cell lines: human embryonic stem cell\u2013derived mesenchymal stem cell line (ES-MSCs) and Infrapatellar fat pad derived MSC (IPFP-MSC) cultured in xeno-free medium. We assessed the biological activity of concentrated cell secretome or isolated fractions of extracellular vesicles (EVs) on cell proliferation, microvascular formation, and cartilage degradation in a human osteoarthritic (OA) ex vivo model. Serum-free conditioned medium from ES-MSC (N = 1) or IPFP-MSC (N = 2) monolayer cultures were concentrated by ultrafiltration to generate concentrated conditioned medium (CCM). Size exclusion chromatography was used to fractionate extracellular vesicles (EVs). Vesicle size, concentration, morphology, and surface markers were characterized by nanoparticle tracking analysis, transmission electron microscopy, and flow cytometry. Biological activity was evaluated by treating human umbilical vein endothelial cells (HUVECs), IPFP-MSCs, and ES-MSCs with CCM and EVs at defined particle concentrations. Endothelial network formation was tested in fibrin gels with different cell and secretome combinations. For analysis of cartilage degradation, human cartilage explants (N = 4; 3.5 mm in diameter) were harvested from patients undergoing total knee arthroplasty and subjected to IL-1\u03b2 stimulation to induce an OA phenotype. Explants were treated with varying doses from CCM or EVs. Release of glycosaminoglycan in the medium and RNA analysis of catabolic genes were used as readouts. Secretome preparations yielded on average approximately 50 billion vesicles per mL with a similar particle size distribution between 50\u2013200 nm in ES-MSC and IPFP-MSC cultures. Transmission electron microscopy confirmed vesicle morphology and flow cytometry confirmed expression of exosomal surface markers (CD9, CD63, CD81). Functionally, CCM and EVs enhanced proliferation in a dose-dependent manner. Endothelial networks formed by HUVECs in fibrin were stabilized over 7 days by CCMs, most notably by hypoxic ES-MSC CCM relative to no CCM treatment (control). In the OA cartilage model, IL-1\u03b2 stimulation increased glycosaminoglycan release, whereas ES-MSC CCM treatment and EV treatment reduced glycosaminoglycan release and ES-MSC CCM reduced gene expression of IL-1\u03b2, MMP-1, and MMP-3. We isolated and characterized the concentrated secretome and the isolated vesicle-enriched fractions from xeno-free ES-MSC and IPFP-MSC and demonstrated bioactivity in promoting cell proliferation, modulating endothelial network formation, and mitigating cartilage degradation in osteoarthritic tissue. These findings support the bioactivity and therapeutic potential of stem cell\u2013derived secretomes for OA.<\/jats:p>","DOI":"10.3390\/ijms27052325","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T12:39:56Z","timestamp":1772455196000},"page":"2325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Anti-Inflammatory and Angiogenic Effects of Stem Cell Secretome"],"prefix":"10.3390","volume":"27","author":[{"given":"Shawn P.","family":"Grogan","sequence":"first","affiliation":[{"name":"Scripps Health, Shiley Center for Orthopaedic Research and Education at Scripps Clinic, 10666 North Torrey Pines Road, MS126, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Stinebaugh","sequence":"additional","affiliation":[{"name":"Scripps Health, Shiley Center for Orthopaedic Research and Education at Scripps Clinic, 10666 North Torrey Pines Road, MS126, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8707-1455","authenticated-orcid":false,"given":"Darryl D.","family":"D\u2019Lima","sequence":"additional","affiliation":[{"name":"Scripps Health, Shiley Center for Orthopaedic Research and Education at Scripps Clinic, 10666 North Torrey Pines Road, MS126, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e13251","DOI":"10.1111\/wrr.13251","article-title":"The Paradigm of Stem Cell Secretome in Tissue Repair and Regeneration: Present and Future Perspectives","volume":"33","author":"Kumar","year":"2025","journal-title":"Wound Repair Regen."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jare.2024.05.004","article-title":"Mesenchymal Stem Cell Secretome for Regenerative Medicine: Where Do We Stand?","volume":"70","author":"Trigo","year":"2025","journal-title":"J. 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