{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T01:03:46Z","timestamp":1777943026747,"version":"3.51.4"},"reference-count":51,"publisher":"SAGE Publications","issue":"9-10","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Shaanxi Provincial Key Research and Development Program","award":["2024SF-GJHX-16"],"award-info":[{"award-number":["2024SF-GJHX-16"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82270551"],"award-info":[{"award-number":["82270551"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program","doi-asserted-by":"crossref","award":["2020YFA0710804"],"award-info":[{"award-number":["2020YFA0710804"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Key Research and Development Program of China","award":["2020YFA0710803"],"award-info":[{"award-number":["2020YFA0710803"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Stem Cells and Development"],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"<jats:p>\n                    Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease lacking effective therapies. Mesenchymal stem cells (MSCs) show therapeutic potential; however, their efficacy is often limited. Aggregates of human umbilical cord-derived MSCs (hUC-MSCs) were generated using AggreWell\u2122 400 plates. The paracrine and mechanotransduction profiles of three-dimensional (3D)-MSCs were assessed by reverse transcription quantitative PCR and western blot. MASH was induced in C57BL\/6J mice via a 32-week high-fat, high-fructose, and high-cholesterol (HFFC) diet, followed by tail vein injection of PBS, two-dimensional (2D)-MSCs, or 3D-MSCs. Therapeutic efficacy was evaluated via histological staining, immunohistochemistry, and serum biochemistry. RNA sequencing was performed to elucidate underlying molecular mechanisms. Under 3D culture conditions, hUC-MSCs formed relatively uniform aggregates with preserved MSC phenotypic characteristics after recovery. 3D aggregate culture enhanced the paracrine, anti-inflammatory, mechanosensitive phenotype, pro-survival, and matrix-remodeling properties of hUC-MSCs, evidenced by increased expression of hepatocyte growth factor, tumor necrosis factor-stimulated gene 6, cyclooxygenase-2, prostaglandin E synthase, B-cell lymphoma-2, and mechanotransduction-related genes, accompanied by elevated matrix metalloproteinase-2 (MMP2) and MMP9 expression\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    .\n                    <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                    fluorescence imaging showed no significant difference in early hepatic retention between intravenously infused single-cell hUC-MSCs and 3D aggregates. In the MASH model, 3D-MSCs more effectively reduced lipid accumulation, collagen deposition, \u03b1-smooth muscle actin, hepatomegaly, and serum total cholesterol levels compared with 2D-MSCs. Moreover, 3D-MSCs enhanced the expression of anti-inflammatory interleukin-10, while suppressing inducible nitric oxide synthase. 3D-MSC therapy induced broader transcriptional remodeling than conventional MSCs, with enrichment in extracellular matrix organization, focal adhesion, and the phosphatidylinositol 3-kinase-protein kinase B signaling pathway. Consistently, western blot analysis showed that 3D-MSCs more effectively reduced hepatic p-PI3K and p-AKT levels, indicating stronger inhibition of PI3K\/AKT pathway activation. 3D aggregate culture enhances the therapeutic efficacy of hUC-MSCs against MASH, supporting its translational potential for MSC-based liver therapy.\n                  <\/jats:p>","DOI":"10.1177\/15473287261442500","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T10:49:26Z","timestamp":1776336566000},"page":"181-193","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Three-Dimensional Aggregate Culture Enhances the Therapeutic Efficacy of Human Umbilical Cord-Derived Mesenchymal Stem Cells in the Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis"],"prefix":"10.1177","volume":"35","author":[{"given":"Chongxiao","family":"Li","sequence":"first","affiliation":[{"name":"Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi\u2019an, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi\u2019an, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erzhuo","family":"Xia","sequence":"additional","affiliation":[{"name":"Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi\u2019an, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyuan","family":"Tian","sequence":"additional","affiliation":[{"name":"Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi\u2019an, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Wang","sequence":"additional","affiliation":[{"name":"Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi\u2019an, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gege","family":"Fu","sequence":"additional","affiliation":[{"name":"Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi\u2019an, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, 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