{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:56:30Z","timestamp":1791644190167,"version":"4.3.4"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008078","name":"University of Strathclyde","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008078","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Dax-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital region on X-chromosome gene 1) blocks 17\u03b2-estradiol biosynthesis and its knockdown would be expected to increase 17\u03b2-estradiol production. We hypothesized that knockdown of Dax-1 in a conditionally immortalized neural stem cell (NSC) line, MHP36, is a useful approach to increase 17\u03b2-estradiol production. Short hairpin (sh) RNA targeted to <jats:italic>Dax-1<\/jats:italic> in NSCs, namely MHP36-Dax1KD cells, resulted in the degradation of <jats:italic>Dax-1<\/jats:italic> RNA and attenuation of Dax-1 protein expression. <jats:italic>In vitro<\/jats:italic>, MHP36-Dax1KD cells exhibited overexpression of aromatase and increased 17\u03b2-estradiol secretion compared to MHP36 cells. As 17\u03b2-estradiol has been shown to promote the efficacy of cell therapy, we interrogated the application of 17\u03b2-estradiol-enriched NSCs in a relevant <jats:italic>in vivo<\/jats:italic> disease model. We hypothesized that MHP36-Dax1KD cells will enhance functional recovery after transplantation in a stroke model. C57BL\/6 male adult mice underwent ischemia\/reperfusion by left middle cerebral artery occlusion for 45 min using an intraluminal thread. Two days later male mice randomly received vehicle, MHP36 cells, MHP36-Dax1KD cells, and MHP36 cells suspended in 17\u03b2-estradiol (100 nm) or 17\u03b2-estradiol alone (100 nm) with serial behavioral testing over 28 days followed by post-mortem histology and blinded analysis. Recovery of sensorimotor function was accelerated and enhanced, and lesion volume was reduced by MHP36-Dax1KD transplants. Regarding mechanisms, immunofluorescence indicated increased synaptic plasticity and neuronal differentiation after MHP36-Dax1KD transplants. In conclusion, knockdown of Dax-1 is a useful target to increase 17\u03b2-estradiol biosynthesis in NSCs and improves functional recovery after stroke <jats:italic>in vivo<\/jats:italic>, possibly mediated through neuroprotection and improved synaptic plasticity. Therefore, targeting 17\u03b2-estradiol biosynthesis in stem cells may be a promising therapeutic strategy for enhancing the efficacy of stem cell-based therapies for stroke.<\/jats:p>","DOI":"10.3389\/fncel.2022.917181","type":"journal-article","created":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T04:36:40Z","timestamp":1658551000000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Targeting 17\u03b2-estradiol biosynthesis in neural stem cells improves stroke outcome"],"prefix":"10.3389","volume":"16","author":[{"given":"Shalmali","family":"Patkar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafe","family":"Uwanogho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Modo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rothwelle J.","family":"Tate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Plevin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary V. 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