{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:10:23Z","timestamp":1787026223168,"version":"build-2736575974"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero Della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The study of age-associated changes in the bone marrow (BM), a key organ for hematopoiesis and immune regulation, is crucial to understanding inflammatory processes linked to cardiovascular diseases. Notably, aging is associated with impaired mobilization of BM-derived cardioprotective CD34\n                      <jats:sup>+<\/jats:sup>\n                      hematopoietic stem\/progenitor cells (HSPCs), resulting in a lower frequency in the circulation and poorer cardiovascular outcomes. HSPCs pharmacological mobilizers (G-CSF, AMD3100) and sympathetic signaling stimulator (norepinephrine, NE) function mainly by acting on CD146\n                      <jats:sup>+<\/jats:sup>\n                      Bone marrow stromal cells (BMSCs), key cellular players in this process. In this study, we developed a human\n                      <jats:italic>in vitro<\/jats:italic>\n                      BM simplified experimental model to assess the impact of aging on CD146\n                      <jats:sup>+<\/jats:sup>\n                      BMSCs in this context.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      CD146\n                      <jats:sup>+<\/jats:sup>\n                      BMSCs were isolated from 29 human subjects, stratified into middle-aged (middle-aged, \u226466 years; N = 13) and older adults (older adult, \u226575 years; N = 16). For functional assays, bone marrow HSPCs from a single donor (female, 64 years) were used. The\n                      <jats:italic>in vitro<\/jats:italic>\n                      BM simplified experimental model was developed by co-culturing CD146\n                      <jats:sup>+<\/jats:sup>\n                      BMSC and CD34\n                      <jats:sup>+<\/jats:sup>\n                      HSPCs in a transwell system. After treatment with mobilizing agents, CD146\n                      <jats:sup>+<\/jats:sup>\n                      BMSCs\u2019 viability, HSPC migration, transcriptome, metabolism, and paracrine activity were assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      AMD3100 enhanced HSPC migration in the model using MA-derived CD146\n                      <jats:sup>+<\/jats:sup>\n                      BMSCs but not in OA-derived cells. RNA sequencing identified 9 age-associated genes, with validated downregulation of\n                      <jats:italic>NRK<\/jats:italic>\n                      and upregulation of\n                      <jats:italic>PDK4<\/jats:italic>\n                      ,\n                      <jats:italic>AQP1<\/jats:italic>\n                      , and\n                      <jats:italic>LMO2<\/jats:italic>\n                      in OA CD146\n                      <jats:sup>+<\/jats:sup>\n                      BMSC. Moreover, a differential gene expression response to mobilizing treatments was observed between groups. Cell-conditioned media from OA CD146\n                      <jats:sup>+<\/jats:sup>\n                      BMSCs showed stronger chemoattractant effects on peripheral blood mononuclear cells and presented increased VCAM-1 levels. No age-related effects on oxidative respiration were observed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      In this study, a BM\n                      <jats:italic>in vitro<\/jats:italic>\n                      co-culture system was developed to study CD146\n                      <jats:sup>+<\/jats:sup>\n                      BMSC-dependent CD34\n                      <jats:sup>+<\/jats:sup>\n                      mobilization in a subject-specific manner, and the complexity of the impact of aging on CD146\n                      <jats:sup>+<\/jats:sup>\n                      BMSC and their response to mobilizing agents was highlighted.\n                    <\/jats:p>\n                  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