Mitochondrial Regulation of Hematopoietic Stem Cells

造血干细胞（HSCs）存在于骨髓（BM）中，处于静止状态，可以自我更新，并生成 造血系统的所有谱系。一幅关于稳态功能和自我平衡 然而，调控HSC的反应的方法尚未出现。此外，虽然取得了进展， 在这一领域，可靠的更新，甚至维持造血干细胞在体外仍然具有挑战性，但将有 重大的翻译影响。一个特别的差距是我们对HSC的细胞器细胞生物学的理解。一 在HSC中的作用尚不清楚的细胞器是线粒体。在干细胞中优先使用糖酵解 表明HSC的线粒体呼吸比祖细胞的更慢。这些发现提出 线粒体是否在HSC中发挥与ATP产生不直接相关的作用， 中间代谢、表观遗传学、细胞凋亡和细胞内钙处理。线粒体动力学 线粒体的融合和分裂，在线粒体功能的协调中发挥核心作用。融合 这一机制由两个部分冗余和相互作用的外膜GTP酶组成，即丝裂融合蛋白（MFN）1 和2，以及内膜GT3，OPA 1。我们观察到，线粒体融合蛋白显示冗余和非- 冗余以及细胞内在和细胞外在的作用，深刻和特异性地影响HSC。我们也 发现HSC具有升高的线粒体质量和减弱的线粒体自噬，并且所有的线粒体融合蛋白 具有严重表型的突变体在HSC中也具有减少的线粒体质量，但在成熟的造血干细胞中没有。 细胞这项提案的目标是阐明潜在的机制和利用线粒体动力学 以实现HSC在体外的更有效维持。

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM), are quiescent, can self-renew, and generate all lineages of the hematopoietic system. A coherent picture of how steady-state function and homeostatic responses of HSCs are regulated has not emerged yet, however. Furthermore, although progress has been made in this area, reliable renewal or even maintenance of HSCs in vitro remains challenging, but would have major translational implications. A particular gap is our understanding of the organellar cell biology of HSCs. One organelle of which role in HSCs is unclear is the mitochondrion. Preferential use of glycolysis in stem cells suggests that mitochondrial respiration is more dispensable for HSCs than for progenitors. These findings raise the question whether mitochondria play roles in HSCs that are not directly related to ATP production, such as intermediary metabolism, epigenetics, apoptosis and intracellular calcium handling. Mitochondria dynamics, the fusion and fission of mitochondria, play a central role in the coordination of mitochondrial function. The fusion machinery consists of two partially redundant and interacting outer membrane GTPases, mitofusins (MFN) 1 and 2, and the inner membrane GTPase, OPA1. We observed that mitofusins show redundant and non- redundant as well as cell-intrinsic and cell-extrinsic roles that profoundly and specifically impact HSCs. We also found that HSCs are endowed with elevated mitochondrial mass and attenuated mitophagy, and that all mitofusin mutants with severe phenotypes also had reduced mitochondrial mass in HSCs, but not in mature hematopoietic cells. The goal of this proposal is to elucidate the underlying mechanisms and harness mitochondrial dynamics to achieve more efficient maintenance of HSC in vitro.