Mitochondrial regulation of hematopoietic stem cells

造血干细胞(HSCs)驻留在骨髓(BM)中，处于静止状态，可以自我更新 生成所有血统的造血系统。尽管我们在认识上取得了重大进展 涉及自我更新、分化和静止的机制，对这些机制是如何 体内HSCs的稳态功能和稳态反应的调节机制协同作用 还没有出现。此外，HSCs在体外的可靠更新还没有实现，而有 强有力的证据表明，HSC的自我更新发生在体内。这意味着，尽管确定了 在基因敲除研究中，数十种细胞因子和200多个影响HSC功能的基因，尽管 关于全基因组表达和表观遗传签名的多项研究的出版，我们的 理解依然存在。一个特别的差距是我们对HSCs的细胞器细胞生物学的理解。HSC依赖于 主要是糖酵解ATP的产生，而许多成熟细胞使用线粒体氧化 磷酸化(OXPHOS)。干细胞糖酵解的优先使用表明线粒体呼吸 对于造血干细胞来说比对于祖细胞来说更可有可无，这一观点得到了实验数据的支持。这些发现 提出一个问题，线粒体是否在HSCs中发挥了与ATP产生没有直接关系的作用。在……里面 除了三磷酸腺苷的产生外，线粒体也是几种生物合成途径和媒介所必需的。 代谢、细胞凋亡和细胞内钙稳态。我们在初步数据中显示， 线粒体在HSCs中以一种特殊的方式受到调节，干扰这种调节会影响 HSC的功能，至少部分是通过缓冲细胞内钙(Ca2+)来实现的，我们发现 造血干细胞与祖细胞和非造血细胞的比较。该提案的目标是更好地定义 HSC中线粒体的调节及其对Ca2+的影响，以及HSC对维持、身份和功能的影响。

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM), are quiescent, can self renew, and generate all lineages of the hematopoietic system. Despite significant progress in our understanding of mechanisms involved in self-renewal, differentiation and quiescence, a coherent picture of how these mechanisms act in concert to regulate steady-state function and homeostatic responses of HSCs in vivo has not emerged yet. Furthermore, reliable renewal of HSCs in vitro has not been achieved, while there is overwhelming evidence that HSC self-renewal occurs in vivo. This implies that despite the identification of dozens of cytokines and of more than 200 genes that affect HSC function in knockout studies, and despite the publication of multiple studies on genome-wide expression and epigenetic signatures, significant gaps in our understanding remain. A particular gap is our understanding of the organellar cell biology of HSCs. HSCs rely predominantly on glycolytic ATP production, while many mature cells use mitochondrial oxidative phosphorylation (OXPHOS). Preferential use of glycolysis in stem cells suggests that mitochondrial respiration is more dispensable for HSCs than for progenitors, a notion supported by experimental data. These findings raise the question whether mitochondria play a role in HSCs that is not directly related to ATP production. In addition to ATP production, mitochondria are also required for several biosynthetic pathways and intermediary metabolism, apoptosis and intracellular calcium homeostasis. We show in our preliminary data that mitochondria are regulated in an exceptional fashion in HSCs, and that interfering with this regulation affects HSC function, at least in part by buffering intracellular calcium (Cai2+), which we found to be strikingly low in HSCs compared to progenitors and non-hematopoietic cells. The goal of is the proposal is to better define regulation of mitochondria in HSC, its impact on Cai2+, and HSC on maintenance, identity and function.