The role of mitochondria in embryonic stem cells.

描述（由申请人提供）：干细胞的特点是其多谱系分化潜力（多能性）和自我更新的能力，这使得它们能够在避免谱系承诺和衰老的同时增殖。人们对确定干细胞在谱系承诺和自我更新的细胞命运之间选择的途径非常感兴趣。更好地理解这一过程将允许开发特定的调节剂来指导干细胞的命运，并提高它们在再生治疗中的效用。最近的研究表明，线粒体功能调节多种细胞类型的基因表达和自我更新，但对线粒体功能在胚胎干细胞中的作用知之甚少。因此，我们研究了人胚胎干细胞（hESCs）的线粒体功能和活性。我们新的初步数据表明，与分化细胞相比，未分化的hESCs具有较高的线粒体生物发生性，但线粒体葡萄糖氧化水平较低。基于我们的数据和最近发表的研究结果，我们提出了葡萄糖氧化调节人类胚胎干细胞（hESCs）自我更新和分化的中心假设。我们建议通过测试以下三个假设来评估这一点：在目的1中，我们将评估调节葡萄糖氧化对hESCs代谢活性的影响。在Aim 2中，我们将评估调节葡萄糖氧化对hESCs自我更新和分化的影响。在Aim 3中，我们将通过使用畸胎瘤形成和血管生成的体内模型来评估增强线粒体葡萄糖氧化如何影响hESC的治疗用途。由于线粒体葡萄糖氧化与人类ESC命运之间尚未明确建立联系，因此该建议研究了一种新的范例。我们的研究结果可能会对细胞代谢和再生过程产生重要的见解。由于多种代谢药理调节剂目前可用并已被批准用于患者，我们相信我们在干细胞生物学中代谢过程的发现可以很容易地转化为临床环境，以改善再生干细胞治疗。

DESCRIPTION (provided by applicant): Stem cells are characterized by their multi-lineage differentiation potential (pluripotency) and their ability for self-renewal, which permits them to proliferate while avoiding lineage commitment and senescence. There has been much interest in identifying the pathways by which stem cells choose between the cell fates of lineage commitment versus self-renewal. A better understanding of this process would allow for the development of specific modulators that direct stem cell fate and improve their utility for regenerative therapies. Recent studies have demonstrated that mitochondrial function regulates gene expression and self-renewal in multiple cell types but little is known about the role of mitochondrial function in embryonic stem cells. We therefore studied the mitochondrial function and activity in human embryonic stem cells (hESCs). Our novel preliminary data suggest that when compared to differentiated cells, undifferentiated hESCs have high mitochondrial biogenesis, but exhibit low levels of mitochondrial glucose oxidation. Based on our data and recent published findings, we have formulated the central hypothesis of the proposal glucose oxidation regulates self-renewal and differentiation of human embryonic stem cells (hESCs). We propose to evaluate this by testing the following three hypotheses: In Aim 1, we will assess the effect of modulating glucose oxidation on the metabolic activity of hESCs. In Aim 2, we will evaluate the effect of modulating glucose oxidation on the self-renewal and differentiation of hESCs. In Aim 3, we will assess how enhancing mitochondrial glucose oxidation affects the therapeutic use of hESC by using in vivo models of teratoma formation and angiogenesis. This proposal investigates a new paradigm, since there is no clearly established link yet between mitochondrial glucose oxidation and human ESC fate. The results from our study of are likely to yield major insights into cellular metabolic and regenerative processes. Since multiple pharmacological modulators of metabolism are currently available and have been approved for use in patients, we believe that our findings on metabolic processes in stem biology could be readily translated into the clinical setting to improve regenerative stem cell therapies.