Mitochondrial regulation of hematopoietic stem cells

造血干细胞的线粒体调控

• 批准号: 9218717
• 负责人: HANS-WILLEM E SNOECK
• 金额: $ 45.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-17 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9218717
• 关键词: Affect; Apoptosis; Autophagocytosis; Biogenesis; Biology; Blood; Bone Marrow; Bone Marrow Transplantation; Buffers; Calcium; Cell Compartmentation; Cell Maintenance; Cell physiology; Cells; Cellular biology; Characteristics; Coupled; Data; Development; Epigenetic Process; Etiology; Gene Expression Profile; Genes; Glycolysis; Goals; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Immune system; In Vitro; Knock-out; Lymphoid; Maintenance; Measures; Mediating; Metabolism; Mitochondria; Mitochondrial DNA; Morphology; Movement; Myelogenous; Organelles; Oxidative Phosphorylation; Pathway interactions; Play; Population; Process; Production; Publications; Regulation; Respiration; Role; Shapes; Stem cells; Testing; cell motility; cost; cytokine; genome-wide; in vivo; leukemia; prevent; progenitor; response; self-renewal

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.

造血干细胞（HSC）存在于骨髓（BM）中，是静止的，可以自我更新， 生成造血系统的所有谱系。尽管我们在理解上取得了重大进展， 机制参与自我更新，分化和静止，一个连贯的画面，这些如何 体内HSC的稳态功能和稳态反应的调节机制 还没有出现。此外，还没有实现HSC在体外的可靠更新，尽管存在 大量证据表明HSC自我更新发生在体内。这意味着，尽管确定了 在敲除研究中，数十种细胞因子和200多个影响HSC功能的基因， 关于全基因组表达和表观遗传特征的多项研究的发表，我们在这方面的重大差距， 理解仍然存在。一个特别的差距是我们对HSC的细胞器细胞生物学的理解。HSC依赖于 主要是糖酵解ATP的生产，而许多成熟细胞使用线粒体氧化 磷酸化（OXPHOS）。在干细胞中优先使用糖酵解表明线粒体呼吸 对HSC比对祖细胞更敏感，这一观点得到了实验数据的支持。这些发现 提出了一个问题，线粒体是否在HSC中发挥作用，这是不直接相关的ATP生产。在 除了ATP的生产，线粒体也需要几个生物合成途径和中介 代谢、细胞凋亡和细胞内钙稳态。我们的初步数据显示， 在HSC中，线粒体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（CaI 2+），我们发现在HSC中CaI 2+的含量非常低。 HSC与祖细胞和非造血细胞相比。该提案的目标是更好地定义 HSC中线粒体的调节、其对Cai 2+的影响以及HSC对维持、身份和功能的影响。