Objective The heart contains a pool of c-kit+ progenitor cells which is believed to be able to regenerate. The differentiation of these progenitor cells is reliant on different physiological cues. Unraveling the underlying signals to direct differentiation of progenitor cells will be beneficial in controlling progenitor cell fate. In this regard, the role of the mitochondria in mediating cardiac progenitor cell fate remains unclear. Specifically, the association between changes in mitochondrial morphology with the differentiation status of c-kit+ CPCs remains elusive. In this study, we investigated the relationship between mitochondrial morphology and the differentiation status of c-kit+ progenitor cells. Methods and Results c-kit+ CPCs were isolated from 2-month-old male wild-type FVB mice. To activate differentiation, CPCs were incubated in α-minimal essential medium containing 10 nM dexamethasone for up to 7 days. To inhibit Drp1-mediated mitochondrial fragmentation, either 10 μM or 50 μM mdivi-1 was administered once at Day 0 and again at Day 2 of differentiation. To inhibit calcineurin, either 1 μM or 5 μM ciclosporin-A (CsA) was administered once at Day 0 and again at Day 2 of differentiation. Dexamethasone-induced differentiation of c-kit+ progenitor cells is aligned with fragmentation of the mitochondria via a calcineurin-Drp1 pathway. Pharmacologically inhibiting mitochondrial fragmentation retains the undifferentiated state of the c-kit+ progenitor cells. Conclusions The findings from this study provide an alternative view of the role of mitochondrial fusion-fission in the differentiation of cardiac progenitor cells and the potential of pharmacologically manipulating the mitochondria to direct progenitor cell fate.

中文翻译：

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钙调神经磷酸酶-Drp1 介导的线粒体断裂与 c-Kit 心肌祖细胞的分化一致。

目的 心脏含有大量被认为能够再生的 c-kit+ 祖细胞。这些祖细胞的分化依赖于不同的生理线索。揭示直接祖细胞分化的潜在信号将有利于控制祖细胞的命运。在这方面，线粒体在介导心脏祖细胞命运中的作用仍不清楚。具体而言，线粒体形态变化与 c-kit+ CPC 分化状态之间的关联仍然难以捉摸。在这项研究中，我们研究了线粒体形态与 c-kit+ 祖细胞分化状态之间的关系。方法和结果 c-kit+ CPCs 是从 2 个月大的雄性野生型 FVB 小鼠中分离出来的。要激活差异化，CPC 在含有 10 nM 地塞米松的 α-最小必需培养基中孵育长达 7 天。为了抑制 Drp1 介导的线粒体断裂，在分化的第 0 天和第 2 天分别施用 10 μM 或 50 μM mdivi-1 一次。为了抑制神经钙蛋白，在分化的第 0 天和第 2 天分别施用 1 μM 或 5 μM 环孢素 A (CsA) 一次。地塞米松诱导的 c-kit+ 祖细胞分化与通过神经钙蛋白-Drp1 途径的线粒体断裂一致。药理学抑制线粒体断裂保留了 c-kit+ 祖细胞的未分化状态。