3,2/-Dihydroxyflavone-Treated Pluripotent Stem Cells Show Enhanced Proliferation, Pluripotency Marker Expression, and Neuroprotective Properties

• Published in: Cell transplantation Vol. 24; no. 8; pp. 1511 - 1532
• Main Authors: Han, Dawoon, Kim, Han Jun, Choi, Hye Yeon, Kim, Bongwoo, Yang, Gwangmo, Han, Jihae, Dayem, Ahmed Abdal, Lee, Hye-Rim, Kim, Jin Hoi, Lee, Kyung-Mi, Jeong, Kyu-Shik, Do, Sun Hee, Cho, Ssang-Goo
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.08.2015; SAGE Publishing
• Subjects: Animals; Axons - physiology; Cell Differentiation - genetics; Cell Line; Cell Lineage; Cell Proliferation - drug effects; Cell Survival - drug effects; Disease Models, Animal; Down-Regulation - drug effects; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Flavonoids - pharmacology; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - transplantation; Male; Mice; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - drug effects; Pluripotent Stem Cells - metabolism; Rats; Rats, Sprague-Dawley; Regeneration; Sciatic Neuropathy - therapy; Transcription Factors - genetics; Transcription Factors - metabolism; Up-Regulation - drug effects; Peripheral nerve injury model; Self-renewal; 3,2′-Dihydroxyflavone; Pluripotent stem cell; Neuroprotective property
• ISSN: 0963-6897; 1555-3892
• DOI: 10.3727/096368914X683511

Efficient maintenance of the undifferentiated status of embryonic stem cells (ESCs) may be important for preparation of high-quality cell sources that can be successfully used for stem cell research and therapy. Here we tried to identify a compound that can enhance the quality of pluripotent stem cells. Treatment of ESCs and induced pluripotent stem cells (iPSCs) with 3,2′-dihydroxyflavone (3,2′-DHF) led to increases in cell growth, colony formation, and cell proliferation. Treatment with 3,2′-DHF resulted in high expression of pluripotency markers (OCT4, SOX2, and NANOG) and significant activation (STAT3 and AKT) or suppression (GSK3β and ERK) of self-renewal-related kinases. 3,2′-DHF-treated high-quality pluripotent stem cells also showed enhanced differentiation potential. In particular, treatment of iPSCs with 3,2′-DHF led to elevated expression of ectodermal differentiation markers and improved differentiation into fully matured neurons. Next, we investigated the in vivo effect of 3,2′-DHF-pretreated iPSCs (3,2′-DHF iPSCs) in a peripheral nerve injury model and found that transplantation of 3,2′-DHF iPSCs resulted in more efficient axonal regeneration and functional recovery than in controls. Upon histopathological and gene expression analyses, we found that transplantation of 3,2′-DHF iPSCs stimulated expression of cytokines, such as TNF-α, in the early phase of injury and successfully reduced convalescence time of the injured peripheral nerve, showing an effective neuroprotective property. Taken together, our data suggest that 3,2′-DHF can be used for more efficient maintenance of pluripotent stem cells as well as for further applications in stem cell research and therapy.