Stem cells and aging

有许多途径和过程似乎可以调节衰老的速度和我们对年龄相关疾病的易感性，如神经变性，动脉粥样硬化和癌症。一个新兴的过程，已越来越多地牵连是耗尽，耗尽或年龄相关的功能障碍的成体干细胞。干细胞为什么或如何衰老的机制尚未得到广泛研究。我们关注细胞内代谢和干细胞衰老之间的联系。我们的假设是，代谢和细胞内活性氧（ROS）的干细胞和祖细胞内的控制是干细胞毒性的关键组成部分。此外，我们假设许多与干细胞调控有关的基因也会影响这些细胞的潜在代谢。 我们最近在Polycomb调节子Bmi 1和细胞内代谢之间建立了有趣的联系（Liu et al.，Nature，2009）。先前的研究表明，Bmi1的缺失导致干细胞自我更新几乎完全失败。因此，Bmi 1活性和Polycomb表观遗传调控是维持造血和神经干细胞区室所必需的。我们的研究结果还表明，Bmi1在调节线粒体功能以及ROS稳态方面具有重要功能。特别是，在缺乏Bmi 1的情况下，ROS水平增加，足以激活DNA损伤反应（DDR）途径。 我们还探索了干细胞生物学和代谢的其他调节因子之间的联系。我们的兴趣之一是Wnt信号通路和代谢之间的联系。我们最近的数据表明，Wnt信号传导在哺乳动物蛋白酶代谢中起重要作用，特别是在肝脏对饥饿的反应中（Liu et al，2011）。 我们目前的努力是使用额外的遗传模型来探索线粒体功能和干细胞功能之间的关系。我们还对干细胞和体细胞组织中氧化还原稳态的调节机制感兴趣。此外，我们正在努力了解代谢在调节干细胞功能的细胞外配体的细胞反应中的作用。

There are many pathways and processes that appear to regulate the rate of aging and our susceptibility to age-related diseases such as neurodegeneration, atherosclerosis and cancer. One emerging process that has been increasingly implicated is the depletion, exhaustion or age-related dysfunction of adult stem cells. The mechanism behind why or how stem cells age has not been extensively studied. We have focused on the connection between intracellular metabolism and stem cell aging. Our hypothesis is that the control of metabolism and intracellular reactive oxygen species (ROS) within stem and progenitor cells is a key component of stem cell maintainence. Furthermore, we hypothesize that many of the genes implicated in stem cell regulation will also influnce the underlying metabolism of these cells. We have recently made an interesting connection between the Polycomb regulator Bmi1 and intracellular metabolism (Liu et al., Nature, 2009). Previous work has demonstrated that the absence of Bmi1 leads to a near total failure of stem cell self-renewal. Thus, Bmi1 activity and by extension Polycomb epigenetic regulation, is required to maintain both the hematopoietic an neural stem cell compartment. Our results also suggested that Bmi1 has important functions in regulating mitochondrial function as well as ROS homeostasis. In particular, in the absence of Bmi1, levels of ROS increase and are sufficient to activate the DNA damage response (DDR) pathways. We have also probed the connection between other regulators of stem cell biology and metabolism. One of our interests has been the connection between the Wnt signaling pathway and metabolism. Our recent data suggest that Wnt signaling plays an important role in mammalain metabolism particularly in the response of the liver to starvation (Liu et al, 2011). Our current efforts are to use additional genetic models to probe the relationship between mitochondrial function and stem cell function. We are also interested in mechanisms that regulate redox homeostasis in stem cells and somatic tissues. In addition, we have ongoing efforts to understand the role of metabolism in the cellular response to extracelluar ligands that regulate stem cell function.