Mitochondrial Regulation of Hematopoietic Stem Cells

造血干细胞的线粒体调节

• 批准号: 10551891
• 负责人: HANS-WILLEM E SNOECK
• 金额: $ 67.57万
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551891
• 关键词: Alleles; Anemia; Apoptosis; Area; Attenuated; Biogenesis; Blood Cells; Bone Marrow; Bone Marrow Cells; Buffers; Calcium; Cell Compartmentation; Cell Maintenance; Cells; Cellular biology; Endowment; Environment; Epigenetic Process; Fetal Liver; Funding; Genetic; Glycolysis; Goals; Guanosine Triphosphate Phosphohydrolases; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; In Vitro; Individual; Interferon alpha; Interferons; Lymphoid; Maintenance; Malignant - descriptor; Mediating; Membrane; Metabolism; Mitochondria; Molecular; Mus; Neonatal Mortality; OPA1 gene; Organelles; Perinatal mortality demographics; Phenotype; Play; Process; Production; Publishing; Regulation; Respiration; Role; STAT1 gene; Signal Induction; Signal Transduction; Site; Testing; epigenetic regulation; experimental study; functional disability; hematopoietic stem cell expansion; hematopoietic stem cell quiescence; microbiome; mitochondrial metabolism; mutant; novel strategies; nuclear factors of activated T-cells; progenitor; reconstitution; response; self-renewal; small molecule; stem cell biology; stem cells

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.

造血干细胞(HSCs)驻留在骨髓(BM)中，处于静止状态，可以自我更新和生成 造血系统的所有血统。一幅关于稳态功能和动态平衡的连贯图景 然而，HSCs的反应受到调控还没有出现。此外，尽管取得了进展，但 在这一领域制造，可靠的更新，甚至在体外维持造血干细胞仍然具有挑战性，但将 主要的翻译含义。一个特别的差距是我们对HSCs的细胞器细胞生物学的理解。一 线粒体在HSCs中的作用尚不清楚。干细胞糖酵解的优先使用 这表明线粒体呼吸对造血干细胞比对祖细胞更可有可无。这些发现提出了 线粒体是否在HSCs中扮演与ATP产生没有直接关系的角色，例如 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，即 线粒体的融合和分裂，在线粒体功能的协调中起着核心作用。核聚变 机械由两个部分冗余和相互作用的外膜GTP酶组成，即有丝分裂素(MFN)1 和2，以及内膜GTP酶OPA1。我们观察到，有丝分裂素显示出冗余和非 以及细胞内部和细胞外部的冗余角色，对HSC产生深远而具体的影响。我们也 发现HSCs具有线粒体质量增加和有丝分裂功能减弱的特点，并且所有的有丝分裂蛋白 具有严重表型的突变体也减少了HSCs中的线粒体质量，但在成熟的造血细胞中则没有 细胞。这项提议的目的是阐明潜在的机制和利用线粒体动力学。 以实现HSC在体外更有效的维护。