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Transplantation of young muscle\u2010derived stem\/progenitor cells (MDSPCs) has shown remarkable therapeutic potential across a range of age\u2010related diseases, primarily through paracrine mechanisms. In this study, secretome profiling of young MDSPCs revealed a unique enrichment of pro\u2010angiogenic and immunomodulatory proteins compared to their aged counterparts. Our systemic transplantation experiments also demonstrate that young MDSPCs activate biological pathways linked to these secreted factors, providing strong mechanistic evidence of their contribution to the reversal of age\u2010associated NM decline at molecular, structural, and functional levels. Systemic transplantation of young MDSPCs into naturally aged mice enhanced motor function and reduced anxiety\u2010like behavior. Structural improvements in aged NM tissues were partially mediated by phosphorylating protein sites involved in muscle neovascularization and regulation of blood\u2013brain barrier integrity in the motor cortex. Paracrine signaling from young MDSPCs enhanced the endogenous regenerative capacity of aged tissues, with effects sustained for up to 2\u2009months post\u2010transplantation. Overall, this study elucidates the molecular basis of MDSPC\u2010mediated NM rejuvenation and provides a foundation for developing novel protein\u2013based therapies to combat age\u2010related functional decline.<\/jats:p>","DOI":"10.1111\/acel.70408","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T10:00:57Z","timestamp":1770890457000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Secretome Profiling of Young Multipotent Stem Cells Reveals Angiogenic and Immunomodulatory Mechanisms Supporting Aged Neuromuscular Health"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6769-6941","authenticated-orcid":false,"given":"Seth D.","family":"Thompson","sequence":"first","affiliation":[{"name":"Shirley Ryan AbilityLab  Chicago Illinois USA"},{"name":"Department of Physical Medicine and Rehabilitation Northwestern University  Chicago Illinois USA"},{"name":"Northwestern University Interdepartmental Neuroscience (NUIN) Graduate Program Northwestern University  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1397-0914","authenticated-orcid":false,"given":"Chelsea L.","family":"Rugel","sequence":"additional","affiliation":[{"name":"Shirley Ryan AbilityLab  Chicago Illinois USA"},{"name":"Department of Physical Medicine and Rehabilitation Northwestern University  Chicago Illinois USA"},{"name":"Northwestern University Interdepartmental Neuroscience (NUIN) Graduate Program Northwestern University  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maddlyn R.","family":"Haller","sequence":"additional","affiliation":[{"name":"Shirley Ryan AbilityLab  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jodi L.","family":"Curtin","sequence":"additional","affiliation":[{"name":"Shirley Ryan AbilityLab  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7534-0497","authenticated-orcid":false,"given":"Sudarshan","family":"Dayanidhi","sequence":"additional","affiliation":[{"name":"Shirley Ryan AbilityLab  Chicago Illinois USA"},{"name":"Department of Physical Medicine and Rehabilitation Northwestern University  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2179-6947","authenticated-orcid":false,"given":"Mitra","family":"Lavasani","sequence":"additional","affiliation":[{"name":"Shirley Ryan AbilityLab  Chicago Illinois USA"},{"name":"Department of Physical Medicine and Rehabilitation Northwestern University  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt514"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1997.sp004012"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-019-2745-x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939886"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201200071"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0602-1"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035273"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.03.001"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","unstructured":"Bogovic J. 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