{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:49:43Z","timestamp":1775980183247,"version":"3.50.1"},"posted":{"date-parts":[[2025,6,1]]},"group-title":"Neuroscience","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T00:00:00Z","timestamp":1748736000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"crossref","award":["W81XWH-22-1-0788"],"award-info":[{"award-number":["W81XWH-22-1-0788"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Amy P. Goldman Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Previous studies on adult mice indicate that the mGluR5 agonist 2-chloro-5-hydroxyphenyl glycine (CHPG), reduces cuprizone-elicited losses in myelin. This effect is partly mediated by CHPG binding to mGluR5 receptors on reactive astrocytes, triggering the release of brain derived neurotrophic factor (BDNF), which results in an increase in myelin, and alleviates behavioral deficits. However, it remains unclear whether CHPG has similar beneficial effects on human cells. To address this issue, we examined effects of CHPG on human cells using both human induced pluripotent stem cell (hiPSC)-derived oligodendrocytes and primary human fetal brain cells. Treatment of hiPSCs (30\u03bcM, 5 days) or primary cells (30 \u03bcM, 3 days) with CHPG increases the percent of MBP\n                  <jats:sup>+<\/jats:sup>\n                  O4\n                  <jats:sup>+<\/jats:sup>\n                  mature oligodendrocytes relative to total O4\n                  <jats:sup>+<\/jats:sup>\n                  cells, without affecting survival. When effects of CHPG were evaluated on proliferating OPCs, effects on proliferation are observed. In contrast, when CHPG was evaluated in young oligodendrocytes, effects on proliferation were gone, suggesting that in this population CHPG is influencing differentiation. Interestingly, in contrast to observations in mice, mGluR5 expression in humans is localized on PDGFR\u03b1\n                  <jats:sup>+<\/jats:sup>\n                  oligodendrocyte precursor cells (OPCs) and O4\n                  <jats:sup>+<\/jats:sup>\n                  immature oligodendrocytes, but not astrocytes. Moreover, using purified human OPC cultures, we show a direct effect of CHPG in enhanced differentiation. To identify potential cellular targets of CHPG in the\n                  <jats:underline>adult<\/jats:underline>\n                  human brain, we analyzed postmortem tissue from individuals with multiple sclerosis (MS) and healthy controls. In contrast to the hiPSCs or fetal cells, demyelinated white matter from MS patients showed elevated mGluR5 mRNA expression in astrocytes. Taken together, our findings suggest that CHPG enhances the differentiation of human OPCs during development through a mechanism distinct from that observed in adult cuprizone-treated mice. Moreover, astrocytes in MS pathology upregulate mGluR5, suggesting they may become responsive to CHPG under disease conditions.\n                <\/jats:p>","DOI":"10.1101\/2025.05.31.656838","type":"posted-content","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T04:20:12Z","timestamp":1748751612000},"source":"Crossref","is-referenced-by-count":1,"title":["The mGluR5 Agonist, CHPG, Enhances Numbers of Differentiated Human Oligodendrocytes"],"prefix":"10.64898","author":[{"given":"Yangyang","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celine","family":"Geywitz","sequence":"additional","affiliation":[{"name":"Interdisciplinary Center for Neurosciences, Heidelberg University, Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anjalika","family":"Bandaru","sequence":"additional","affiliation":[{"name":"School of Environmental and Biological Sciences, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian A.","family":"Glass","sequence":"additional","affiliation":[{"name":"University of Washington, Seattle, WA 98105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Birth Defects Research Laboratory","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-4116","authenticated-orcid":false,"given":"Lucas","family":"Schirmer","sequence":"additional","affiliation":[{"name":"Interdisciplinary Center for Neurosciences, Heidelberg University, Mannheim, Germany"},{"name":"Division of Neuroimmunology, Department of Neurology, Heidelberg University, Mannheim, Germany"},{"name":"Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Heidelberg University, Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Nobuta","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ 08854, USA"},{"name":"Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheryl","family":"Dreyfus","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ 08854, 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