{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:04:40Z","timestamp":1784804680773,"version":"3.55.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Frailty associated with aging, characterized by chronic inflammation and immune dysfunction, poses a significant public health challenge. Human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) exhibit immunomodulatory properties; however, their mechanism of action in frail elderly populations remains unclear. Building on a prior clinical trial investigating HUC-MSCs for elderly frailty (Trial Registration: ClinicalTrials.gov, NCT04314011; PubMed ID: 38679727), this study was conducted to further elucidate the mechanism of action of HUC-MSCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a longitudinal single-cell RNA sequencing (scRNA-seq) study on peripheral blood mononuclear cells (PBMCs) from frail elderly patients before and after HUC-MSCs therapy. Immune cell dynamics were analyzed across multiple time points, and cell-cell communication networks were reconstructed. Spearman correlation analyses were performed to link immune changes with clinical frailty and physical performance metrics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HUC-MSCs induced a time-dependent recalibration of the immune system. An early, transient expansion of MAIT cells (p=0.049) was followed by a sustained reduction in B cell hyperactivity (p=0.032) and a phenotypic shift in na\u00efve B cells. NK cell cytotoxicity was enhanced (increased GNLY), while NKT cells showed modulated stress-response signatures. Cell-cell communication was reorganized, with the EPHA\/NRG pathways highlighting CD4\n                      <jats:sup>+<\/jats:sup>\n                      TEM, MAIT, and NKT cells as central signaling hubs. Critically, these immunomodulatory changes were quantitatively associated with clinical improvement: reductions in B cell and innate immune subsets correlated with gains in grip strength and gait speed, while regulatory T cell expansion was linked to improved lower-limb function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HUC-MSCs restore immune homeostasis in aging frailty through sequential, multi-faceted immunomodulation. The association between specific immune remodeling features and functional recovery positions HUC-MSCs as a promising mechanism-based therapy for aging frailty.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1796161","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:23:16Z","timestamp":1783923796000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunomodulatory effects of HUC-MSCs therapy: enhancing adaptive and innate immune responses in aging frailty"],"prefix":"10.3389","volume":"17","author":[{"given":"Ce","family":"Huang","sequence":"first","affiliation":[{"name":"Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]},{"name":"Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingqian","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]},{"name":"Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Gong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization of Ministry of Education, College of Life Sciences, Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyu","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangying","family":"Huo","sequence":"additional","affiliation":[{"name":"Institute of Advanced Biotechnology and School of Medicine, Southern University of Science and Technology","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]},{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization of Ministry of Education, College of Life Sciences, Shihezi University","place":["Shihezi, China"]},{"name":"Institute of Advanced Biotechnology and School of Medicine, Southern University of Science and Technology","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]},{"name":"Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongmin","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(19)31785-4","article-title":"Management of frailty: opportunities, challenges, 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