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This poses a major challenge for widespread clinical application. We explored a novel strategy for placenta-derived MSCs combining 2D expansion with 3D spheroid culture to address these limitations. Our research shows that culturing MSCs as 3D spheroids significantly reduces individual cell size and size distribution compared to 2D culture. Spheroid formation is feasible in chemically defined media with minimal cell death, and is enhanced by extracellular matrix protein supplementation. Although MSCs do not proliferate in 3D suspension, an alternating 2D\/3D culture protocol, transitioning cells between 2D flasks and 3D spheroids after each passage, effectively slows MSC enlargement and senescence over long periods. This alternating method also preserves MSC immunomodulatory function, unlike continuous 2D culture which leads to its loss. For scalability, we developed an RGD-functionalized alginate hydrogel tube (AlgTube) system that mimics this alternating environment, supporting both adherent growth and chemically triggered spheroid formation. This alternating 2D\/3D culture strategy and the scalable AlgTube platform provide a foundation for developing next-generation MSC manufacturing technologies to meet future clinical demands.<\/jats:p>","DOI":"10.1101\/2025.05.20.655182","type":"posted-content","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T15:05:12Z","timestamp":1748185512000},"source":"Crossref","is-referenced-by-count":1,"title":["Alternating 2D and 3D Culture Reduces Cell Size and Extends the Lifespan of Placenta-Derived MSCs"],"prefix":"10.64898","author":[{"given":"Ying","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Pennsylvania State University, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Pennsylvania State University, PA, USA"},{"name":"Huck Institutes of Life Sciences, Pennsylvania State University, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yakun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Pennsylvania State University, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinran","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Pennsylvania State University, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2985-3627","authenticated-orcid":false,"given":"Aijun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA"},{"name":"Center for Surgical Bioengineering, Department of Surgery, University of California, Davis, School of Medicine, Sacramento, CA, USA"},{"name":"Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangqi","family":"Xie","sequence":"additional","affiliation":[{"name":"Cancer Biology and Infection Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wuqiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Physiology and Biomedical Engineering, Center for Regenerative Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7382-5378","authenticated-orcid":false,"given":"Shue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Chemical and Biomedical Engineering, University of New Haven, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuguo","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Pennsylvania State University, PA, USA"},{"name":"Huck Institutes of Life Sciences, Pennsylvania State University, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041123200840000_2025.05.20.655182v1.1","doi-asserted-by":"crossref","unstructured":"Pittenger, M. 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