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Selective eradication of pluripotent stem cells by inhibiting DHODH activity

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Title: Selective eradication of pluripotent stem cells by inhibiting DHODH activity
Authors: Kondo, Toru Browse this author →KAKEN DB
Keywords: brequinar (BRQ)
cell therapy
dihydroorotate dehydrogenase (DHODH)
mouse pluripotent stem cells (mPSCs)
regenerative medicine
Issue Date: Jan-2021
Publisher: John Wiley & Sons
Journal Title: Stem cells
Volume: 39
Issue: 1
Start Page: 33
End Page: 42
Publisher DOI: 10.1002/stem.3290
Abstract: Pluripotent stem cells (PSCs), such as embryonic stem cells and induced pluripotent stem cells, give rise to all kinds of functional cells, making them promising for successful application in regenerative medicine. However, there is concern that a PSC-derived differentiated cell population may form teratomas when used for cell therapy if the population contains undifferentiated PSCs. Therefore, for the success of regenerative medicine, it is crucial to establish methods that induce complete PSC differentiation and eliminate the contamination of PSCs. Here, I show that the dihydroorotate dehydrogenase (DHODH) inhibitor brequinar (BRQ) induced cell cycle arrest, cell death, and stemness loss in mouse PSCs (mPSCs), whereas it was less toxic against normal tissue-specific stem cells and differentiating cells. I demonstrate that BRQ-pretreated mPSCs did not form teratomas after being transplanted into NOD/SCID mice. Moreover, BRQ administration to teratoma-bearing mice prevented tumor growth and decreased PSC marker levels in the tumor without any visible effects in the differentiated germ layer cells and the mice. Collectively, these data suggested that DHODH inhibitors such as BRQ can be indispensable in the fundamental methods of PSC-based therapy.
Rights: Kondo, T. Selective eradication of pluripotent stem cells by inhibiting DHODH activity. Stem Cells. 2021; 39: 33–42. © 2020 AlphaMed Press
Type: article (author version)
Appears in Collections:遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 近藤 亨

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