期刊
AGING-US
卷 4, 期 6, 页码 393-401出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100465
关键词
mitochondrial division regulates somatic cell reprogramming
资金
- Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo, Fondo de Investigacion Sanitaria (FIS), Spain) [CP05-00090, PI06-0778, RD06-0020-0028]
- Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (AECC, Spain)
- Ministerio de Ciencia e Innovacion (MICINN, Spain) [SAF2009-11579]
- Ministerio de Sanidad y Consumo, Fondo de Investigacion Sanitaria -FIS-, Spain [CD08/00283]
- Ministerio de Ciencia e Innovacion (MICINN, Spain)
Recent studies have suggested a pivotal role for autophagy in stem cell maintenance and differentiation. Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) has been also suggested to bio-energetically take advantage of mitochondrial autophagy (mitophagy). We have preliminary addressed how mitophagy might play a role in the regulation of induced pluripotency using mdivi-1 (for mitochondrial division inhibitor), a highly efficacious small molecule that selectively inhibits the self-assembly of DRP1, a member of the dynamin family of large GTPases that mediates mitochondrial fission. At mdivi-1 concentrations that rapidly induced the formation of mitochondrial net-like or collapsed perinuclear mitochondrial structures, we observed that the reprogramming efficiency of mouse embryonic fibroblasts transduced with the Yamanaka three-factor cocktail (OCT4, KLF4, and SOX2) is drastically reduced by more than 95%. Treatment of MEFs with mdivi-1 at the early stages of reprogramming before the appearance of iPSC colonies was sufficient to completely inhibit somatic cell reprogramming. Therefore, the observed effects on reprogramming efficiencies were due likely to the inhibition of the process of reprogramming itself and not to an impairment of iPSC colony survival or growth. Moreover, the typical morphology of established iPSC colonies with positive alkaline phosphatase staining was negatively affected by mdivi-1 exposure. In the presence of mdivi-1, the colony morphology of the iPSCs was lost, and they somewhat resembled fibroblasts. The alkaline phosphatase staining was also significantly reduced, a finding that is indicative of differentiation. Our current findings provide new insight into how mitochondrial division is integrated into the reprogramming factors-driven transcriptional network that specifies the unique pluripotency of stem cells.
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