{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:01:17Z","timestamp":1780290077764,"version":"3.54.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>\n                    Aging and neurodegenerative disorders like Alzheimer\u2019s Disease (AD) are associated with progressive dysfunction of the blood-brain barrier (BBB) and neurovascular unit (NVU), contributing to impaired vascular integrity and neuronal vulnerability. Apolipoprotein E (APOE) is a key regulator of neurovascular function, and the rare\n                    <jats:italic>APOE3-R136S<\/jats:italic>\n                    \u201cChristchurch\u201d variant (\n                    <jats:italic>APOE3Ch<\/jats:italic>\n                    ) confers protection against AD. Mesenchymal stromal cells (MSCs) represent a promising cell-based therapy for the treatment of neurodegenerative diseases due to their paracrine effect exerted on vascular and neural cells. To investigate how\n                    <jats:italic>APOE3Ch<\/jats:italic>\n                    influences MSC-mediated neurovascular support, we used isogenic iPSC-derived MSCs (iMSCs) with homozygous\n                    <jats:italic>APOE3Ch<\/jats:italic>\n                    or\n                    <jats:italic>APOE3<\/jats:italic>\n                    . We found that\n                    <jats:italic>APOE3Ch<\/jats:italic>\n                    iMSCs have stronger immunosuppressive effect on LPS-induced NF\u03baB activation of THP1 cells.\n                    <jats:italic>APOE3Ch<\/jats:italic>\n                    iMSCs also enhanced endothelial barrier resistance and angiogenic capacity compared to\n                    <jats:italic>APOE3<\/jats:italic>\n                    iMSCs when directly co-cultured with endothelial cells. In addition, conditioned medium from\n                    <jats:italic>APOE3Ch<\/jats:italic>\n                    iMSCs promoted neurite outgrowth more efficiently than that from\n                    <jats:italic>APOE3<\/jats:italic>\n                    iMSCs. Metabolic profiling revealed differences between\n                    <jats:italic>APOE3Ch<\/jats:italic>\n                    and\n                    <jats:italic>APOE3<\/jats:italic>\n                    iMSCs, suggesting altered metabolic resilience. Together, these findings demonstrate that iMSCs support vascular and neuronal function through paracrine mechanisms and suggest that\n                    <jats:italic>APOE3Ch<\/jats:italic>\n                    variant improves specific aspects of MSC-mediated neurovascular support. This work highlights the potential of combining MSC-based therapies with protective\n                    <jats:italic>APOE<\/jats:italic>\n                    variants to target BBB and NVU dysfunction in aging and neurodegeneration.\n                  <\/jats:p>","DOI":"10.3389\/fmolb.2026.1778856","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T04:19:28Z","timestamp":1780287568000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells"],"prefix":"10.3389","volume":"13","author":[{"given":"Paula J.","family":"Rodriguez Martinez","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aria R.","family":"Yslas","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuteru","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammee M.","family":"Parsons","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic","place":["Jacksonville, FL, United States"]},{"name":"Mayo Clinic Center for Regenerative Biotherapeutics","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha K.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic","place":["Jacksonville, FL, United States"]},{"name":"Mayo Clinic Center for Regenerative Biotherapeutics","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana-Caroline","family":"Raulin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahisa","family":"Kanekiyo","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic","place":["Jacksonville, FL, United States"]},{"name":"Mayo Clinic Center for Regenerative Biotherapeutics","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1038\/s41591-019-0611-3","article-title":"Resistance to autosomal dominant alzheimer's disease in an APOE3 Christchurch homozygote: a case report","volume":"25","author":"Arboleda-Velasquez","year":"2019","journal-title":"Nat. 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