Mitochondrial Regulation of Hematopoietic Stem Cells

造血干细胞的线粒体调节

• 批准号: 10375950
• 负责人: HANS-WILLEM E SNOECK
• 金额: $ 68.96万
• 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/10375950
• 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; 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 Transduction; Site; Testing; epigenetic regulation; experimental study; functional disability; hematopoietic stem cell expansion; hematopoietic stem cell quiescence; microbiome; mitochondrial metabolism; mutant; novel strategies; 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（HSC）位于骨髓（BM）中，是静止的，可以自我更新并产生 造血系统的所有谱系。稳态功能和体内稳态的一致图片 但是，HSC的响应尚未出现。此外，尽管进步已经 在这一领域制造，在体外的可靠更新甚至维护HSC仍然具有挑战性，但 主要的翻译含义。一个特殊的差距是我们对HSC的细胞器细胞生物学的理解。一 线粒体在HSC中的作用尚不清楚。在干细胞中优先使用糖酵解 表明线粒体呼吸对HSC比祖细胞更容易获得。这些发现提出了 线粒体是否在与ATP生产无直接相关的HSC中扮演角色的问题，例如 中介代谢，表观遗传学，凋亡和细胞内钙处理。线粒体动力学 线粒体的融合和裂变在线粒体功能的协调中起着核心作用。融合 机械由两个部分冗余和相互作用的外膜GTPase组成 和2，以及内膜GTPase，OPA1。我们观察到丝属素显示出冗余和非 - 冗余以及细胞中的和细胞 - 超支作用，对HSC产生深远，特别影响的影响。我们也是 发现HSC赋予线粒体质量升高并减弱线粒体，并且所有线粒体 患有严重表型的突变体也减少了HSC中的线粒体质量，但在成熟的造血中也没有降低 细胞。该建议的目的是阐明潜在的机制和线束线粒体动力学 为了实现体外HSC的更有效维护。