The Mitochondrial Electron Transport Chain Is Dispensable for Proliferation and Differentiation of Epidermal Progenitor Cells
The Mitochondrial Electron Transport Chain Is Dispensable for Proliferation and Differentiation of Epidermal Progenitor Cells
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DOI：
10.1002/stem.695
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发表时间：
2011-09-01
期刊：
影响因子：
5.2
通讯作者：
Wiesner, Rudolf J.
中科院分区：
文献类型：
--
作者：
Baris, Olivier R.;Klose, Anke;Wiesner, Rudolf J.
组织干细胞和生殖系或胚胎干细胞具有降低氧化代谢的作用，这被认为是减少由活性氧引起的损伤积累的一种适应性机制。然而，另一种解释是，与分化细胞相比，干细胞对特殊细胞质功能的依赖较少，因此具有高核质体积比，因此线粒体含量较低。为了确定干细胞是否依赖线粒体呼吸，我们选择性地消融了表皮基底层的电子传输链，其中包括表皮祖细胞/干细胞(EPSCs)。这是通过使用loxP侧翼线粒体转录因子A(TfAM)等位基因和角蛋白14 Cre转基因来实现的。这些动物(Tfam(EKO))的表皮显示线粒体DNA严重枯竭，完全没有呼吸链复合体。然而，尽管由于营养不良而寿命较短，但表皮发育和皮肤屏障功能并未受到损害。表皮层分化正常，未见明显的增殖缺陷或细胞凋亡增加。相比之下，体内线粒体膜上的支架蛋白-2被表皮切除的小鼠，表现出在子宫中就可以观察到的戏剧性表型，皮肤结构和屏障功能严重受损，最终导致出生后不久脱水死亡。总而言之，我们在这里提供了明确的证据，表明EPSCs，可能还有一般的组织干细胞，是独立于线粒体呼吸链的，但仍然需要一个功能性的动态线粒体间隔。干细胞2011；29：1459-1468
Tissue stem cells and germ line or embryonic stem cells were shown to have reduced oxidative metabolism, which was proposed to be an adaptive mechanism to reduce damage accumulation caused by reactive oxygen species. However, an alternate explanation is that stem cells are less dependent on specialized cytoplasmic functions compared with differentiated cells, therefore, having a high nuclear-to-cytoplasmic volume ratio and consequently a low mitochondrial content. To determine whether stem cells rely or not on mitochondrial respiration, we selectively ablated the electron transport chain in the basal layer of the epidermis, which includes the epidermal progenitor/stem cells (EPSCs). This was achieved using a loxP-flanked mitochondrial transcription factor A (Tfam) allele in conjunction with a keratin 14 Cre transgene. The epidermis of these animals (Tfam(EKO)) showed a profound depletion of mitochondrial DNA and complete absence of respiratory chain complexes. However, despite a short lifespan due to malnutrition, epidermal development and skin barrier function were not impaired. Differentiation of epidermal layers was normal and no proliferation defect or major increase of apoptosis could be observed. In contrast, mice with an epidermal ablation of prohibitin-2, a scaffold protein in the inner mitochondrial membrane, displayed a dramatic phenotype observable already in utero, with severely impaired skin architecture and barrier function, ultimately causing death from dehydration shortly after birth. In conclusion, we here provide unequivocal evidence that EPSCs, and probably tissue stem cells in general, are independent of the mitochondrial respiratory chain, but still require a functional dynamic mitochondrial compartment. STEM CELLS 2011;29:1459-1468