The role of mitochondria in hematopoietic stem cell self-renewal

摘要 造血干细胞(HSC)通过以下方式维持一生中所有血液和免疫细胞的产生 分化为所有血统，再生长寿的HSC，即自我更新。然而，尽管HSC 具有很高的再生潜力，即具有自我更新能力的子代细胞 相同的属性是有限的。已知，随着分裂，HSC逐渐失去再生潜能 历史。对体内平衡状态下HSC功能下降的机制有清晰的认识 条件还不具备。这种知识的缺乏阻碍了我们维持HSC功能的能力 组织。这项拨款申请的总体目标是了解哪些生理机制获得 在具有复制的HSC中触发，从而减少HSC池的活动。我们发现有一次 肝星状细胞被激活，线粒体不可逆转地重塑，不会回到动态平衡状态。肝星状细胞 由于线粒体质量控制的进行性下降而积累功能障碍的线粒体 机制，包括减少线粒体周转和动力，使HSCs携带线粒体 在形状和功能上有所不同。从机制上讲，HSC失去线粒体的分裂活性[即，丧失 分裂调节因子Drp1活性]，这会导致HSC再生潜力下降。我们假设 在稳态条件下，HSC线粒体重塑导致HSC功能下降。主 本提案的目标是了解质量如何变化的贡献和机制 决定了HSC的功能。AIM1将进一步研究线粒体动力学的变化 和人员流动改变了HSC的功能。我们将通过HSC复制来检查线粒体重塑及其影响 它对HSC功能有影响；从机制上确定哪些分子途径驱动线粒体缺陷和 HSC磨损；在生理学相关模型中确定线粒体在人类HSC中的作用。AIM2将 研究HSCs线粒体质量控制丧失的机制，重点是 心磷脂。我们将研究心磷脂作为HSCs线粒体功能障碍的原因因素的作用。我们 将在体内测试补充脂质改善HSC功能的治疗潜力。 拟议的研究提供了一个独特的机会来检查异常的具体贡献 在动态平衡条件下，线粒体对HSC的功能随着分裂而下降。它将进行调查 HSCs积累功能障碍的线粒体以驱动其功能衰退的新概念 动态平衡条件，可能作为HSC内部生物钟的一种手段，这可能导致识别 通过分裂维持HSC功能的药物干预的新方法。

Abstract Hematopoietic stem cells (HSC) sustain the production of all blood and immune cells throughout life by differentiating into all blood lineages and regenerate long-lived HSC, ie self-renew. However, although HSC have high regenerative potential, the actual capacity of ‘self-renewal’, ie regenerating a daughter cell that has identical properties’ is limited. It is known that HSC progressively lose regenerative potential with divisional history. A clear understanding of the mechanism responsible for HSC functional decline under homeostatic conditions is still lacking. This lack of knowledge has hampered our ability to maintain HSC functions through divisions. The overall goal of this grant application is to understand which physiological mechanisms get triggered in HSCs with replication, which reduce the activity of the HSC pool. We have discovered that once HSCs get activated, mitochondria irreversibly remodel and do not return to homeostatic conditions. HSCs accumulate dysfunctional mitochondria due to a progressive decline in mitochondrial quality control mechanisms, including reduced mitochondrial turnover and dynamism such that HSCs carry mitochondria have that are different in shape and functions. Mechanistically, HSC lose mitochondrial fission activity [ie, loss of the fission regulator Drp1 activity], which causes a decrease in HSC regenerative potential. We hypothesize that HSC mitochondrial remodeling drives HSC functional decline under homeostatic conditions. The main objectives of this proposal are to understand the contribution and mechanisms of how changes in the quality of mitochondria determine HSC functions. Aim1 will further investigate how a change in mitochondrial dynamism and turnover alter HSC functions. We will examine mitochondria remodeling with HSC replication and the impact it has on HSC functions; mechanistically determine which molecular pathways drive mitochondrial defects and HSC attrition; determine the role of mitochondria in human HSC in physiologically relevant models. Aim2 will investigate mechanisms responsible for the loss of mitochondrial quality controls in HSCs with a focus on cardiolipin. We will examine the role of cardiolipin as causal factor of mitochondrial dysfunctions in HSCs. We will test therapeutic potentials for lipid supplementation in ameliorating HSC functions in vivo. The proposed studies provide a unique opportunity to examine the specific contribution of abnormal mitochondrial functions to HSC functional decline with divisions under homeostatic conditions. It will investigate the novel concept that HSCs accumulate dysfunctional mitochondria to drive their functional decline under homeostatic conditions, perhaps as a mean of HSC internal biological clock, which may lead to the identification of novel approaches for pharmacological intervention to maintain HSC functions through divisions.