A Flavonoid Compound Promotes Neuronal Differentiation of Embryonic Stem Cells via PPAR-β Modulating Mitochondrial Energy Metabolism.
Relatively little is known regarding mitochondrial metabolism in neuronal differentiation of embryonic stem (ES) cells. By using a small molecule, present research has investigated the pattern of cellular energy metabolism in neural progenitor cells derived from mouse ES cells. Flavonoid compound 4a faithfully facilitated ES cells to differentiate into neurons morphologically and functionally. The expression and localization of peroxisome proliferator-activated receptors (PPARs) were examined in neural progenitor cells. PPAR-β expression showed robust upregulation compared to solvent control. Treatment with PPAR-β agonist L165041 alone or together with compound 4a significantly promoted neuronal differentiation, while antagonist GSK0660 blocked the neurogenesis-promoting effect of compound 4a. Consistently, knockdown of PPAR-β in ES cells abolished compound 4a-induced neuronal differentiation. Interestingly, we found that mitochondrial fusion protein Mfn2 was also abolished by sh-PPAR-β, resulting in abnormal mitochondrial Ca2+ ([Ca2+]M) transients as well as impaired mitochondrial bioenergetics. In conclusion, we demonstrated that by modulating mitochondrial energy metabolism through Mfn2 and mitochondrial Ca2+, PPAR-β took an important role in neuronal differentiation induced by flavonoid compound 4a.
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Yu-Qin
YQ
Mei
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Zong-Fu
ZF
Pan
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Wen-Teng
WT
Chen
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Min-Hua
MH
Xu
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Dan-Yan
DY
Zhu
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Yong-Ping
YP
Yu
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Yi-Jia
YJ
Lou
D000818:Animals; D002118:Calcium; D002454:Cell Differentiation / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005419:Flavonoids / Q000008:administration & dosage*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics; D048068:PPAR-beta / Q000096:biosynthesis* / Q000235:genetics
D005419:Flavonoids; D047495:PPAR gamma; D048068:PPAR-beta; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; D002118:Calcium