Towards Understanding Molecular Mechanisms of Human Hematopoietic Stem Cells' Quiescence

理解人类造血干细胞静止的分子机制

• 批准号: 10346063
• 负责人: SAGHI GHAFFARI
• 金额: $ 33.8万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10346063
• 关键词: Age; Autophagocytosis; Blood; Cell Cycle; Cell Surface Receptors; Cell Therapy; Cells; Clinic; Communication; Disease; Foundations; Generations; Genomics; Goals; Health; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cell subsets; Hematopoietic stem cells; Homeostasis; Human; Image; Injury; Intervention; Life; Link; Longevity; Lysosomes; Maintenance; Malignant Neoplasms; Mediating; Membrane Potentials; Metabolic stress; Mitochondria; Molecular; Mus; Organelles; Output; Pathway interactions; Phenotype; Pluripotent Stem Cells; Process; Property; Recycling; Regulation; Surface; Testing; Time; Tissues; Translations; Transplantation; Work; adult stem cell; base; design; hematopoietic stem cell fate; hematopoietic stem cell quiescence; improved; in vivo; mitochondrial membrane; novel; novel strategies; programs; repaired; replication stress; response; self-renewal; stem cell engraftment; stem cell function; stem cell therapy; stem cells; stem-like cell; success; therapy resistant

SUMMARY/ABSTRACT Hematopoietic stem cells (HSCs) produce all blood lineages and replenish blood in response to loss or injury throughout life. HSCs like most adult stem cells, are mainly quiescent. Quiescence is proposed to protect HSCs from replicative and metabolic stress that would otherwise impact health and longevity, thereby enabling them to maintain tissue homeostasis and allowing for the repair of defective/damaged tissue during their lifetime. Progress in HSC-based therapies is partly hindered by lack of reliable approaches to modulate HSC quiescence and activity. Thus, understanding the core molecular mechanisms of HSC quiescence is fundamental for improving HSC health and longevity and has major translational implications for the clinic. By applying a new approach based on mitochondrial membrane potential (MMP), we identified the most dormant subsets of both human and mouse HSCs. Using this approach, we recently discovered that lysosomal activity is pivotal for the maintenance of mouse HSC quiescence. Our findings suggest that lysosomes dynamically regulate the hematopoietic stem cell switch between quiescent and active states. Here, we propose to investigate lysosomal function and the effects of modulation of lysosomal activity on the potency of human HSCs. These studies are likely to provide means towards extending the availability of human HSCs. Overall, translation of our findings to human HSCs will build the foundation towards advancing cell therapy.

摘要/摘要 造血干细胞 (HSC) 产生所有血统并补充血液以应对损失或受伤 一生。与大多数成体干细胞一样，HSC 主要处于静止状态。建议静止以保护 HSCs 免受复制和代谢压力的影响，否则会影响健康和寿命，从而 使它们能够维持组织稳态并允许修复有缺陷/受损的组织 他们的一生。基于 HSC 的疗法的进展部分由于缺乏可靠的调节方法而受到阻碍 HSC 静止和活动。因此，了解 HSC 静止的核心分子机制是 是改善 HSC 健康和寿命的基础，对临床具有重大转化意义。 通过应用基于线粒体膜电位 (MMP) 的新方法，我们确定了最 人类和小鼠 HSC 的休眠子集。使用这种方法，我们最近发现 溶酶体活性对于维持小鼠 HSC 静止至关重要。我们的研究结果表明 溶酶体动态调节造血干细胞在静止和活跃状态之间的转换。 在这里，我们建议研究溶酶体功能以及溶酶体活性调节对 人类 HSC 的效力。这些研究可能会提供扩大可用性的方法 人类造血干细胞。总体而言，将我们的研究结果转化为人类 HSC 将为进一步发展奠定基础 细胞疗法。