PPAR-γ Agonist Promotes Proliferation of Neural Stem Cells Via Mitophagy Inhibition

Abstract

Background: Proliferation of neural stem cells (NSCs) is crucial for recovery from spinal cord injury (SCI). The effect of PPAR-γ agonist on SCI recovery and the way it regulating NSCs proliferation are both unknown. Methods: The effects of PPAR-γ agonist (rosiglitazone) treatment on recovery from SCI and proliferation of NSCs were confirmed. The roles of mitophagy and PTEN induced putative kinase 1 (PINK1) in rosiglitazoneinduced proliferation of NSCs were explored. Details mechanisms on the transcription regulation of PINK1 by rosiglitazone were addressed. Findings: Rosiglitazone independently increased the proportion of Nestin /Brdu cells in the spinal cord and motor function of SCI rats. It reduced mitophagy and expression of PTEN induced putative kinase 1 (PINK1) in NSCs. The forkhead box protein O1 (FOXO1) was identified as the transcription factor mostly altered by rosiglitazone. Restoration of FOXO1 expression antagonized the effects of rosiglitazone on mitophagy and PINK1 expression. The FOXO1 consensus sequence (FCS) was not identified upstream of the PINK1 transcription start site, but three FCSs were found in the first intron of the PINK1 gene. All of the FCSs participated in the regulation of PINK1 transcription upon treatment with rosiglitazone and expression of FOXO1 but the proximal FCS (chr 5: 156680169-156680185, 3022 bp counting from the translation start site) exerted greater influence. Conclusions: PPAR-γ agonist could be a promising therapeutic strategy for spinal cord injury. Funding Statement:This work was supported by the National Natural Science Foundation of China (Grant No. 81870334, 81301038, 81300071, 81300279 and 81741067); the Science and Technology Program of Guangdong (Grant No. 2015A020212029); and the Science and Technology Program of Guangzhou City (Grant No. 201510010048, 201607010009, 201607010010 and 201804010050). Declaration of Interests: All authors declare no potential conflict of interest. Ethics Approval Statement: All of the animal experiments complied with the ARRIVE guidelines, and they were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 8023, revised 1978)