Deciphering the development of hematopoietic stem and progenitor cell self-renewal and differentiation

项目摘要 造血干/祖细胞具有自我更新和多向分化潜能 分化能力。因此，它们产生所有成熟的血细胞类型（例如，骨髓、淋巴和 红细胞）以维持终生造血。它们的再生能力使HSPC对细胞有价值 血液病患者的替代治疗，包括继发于 化疗和放疗。了解HSPC的自我更新和多能性特性， 开发方法，以改善和最大限度地发挥其治疗潜力。通过研究胚胎 HSPC自我更新和分化能力的起源，我们的目标是推进关于这些的知识 定义干细胞的特征。除了HSPC，还产生了其他多谱系祖细胞 在胚胎发育过程中。这些在自我更新和分化输出方面是有限的， 在本质上被认为是短暂的。这些祖细胞群体具有干细胞的许多特征， HSPC在其天然胚胎环境中的性质的研究。在小鼠和 斑马鱼模型表明，这些胚胎祖细胞，而不是HSPCs，是优势种群 在胚胎中产生成熟的血细胞。如果HSPC不是维持胚胎所必需的，那么它们的 在发展过程中，？为了回答这个问题，我们建议使用斑马鱼来确定何时和 其中在发育期间HSPC自我更新并有助于骨髓，淋巴， 和红细胞谱系。我们将使用新的再生和移植试验（目的1）来研究自我- 更新和谱系追踪实验（目的2）以研究HSPC分化。了解这些 建立和维持干细胞的特性对于利用干细胞进行再生医学至关重要。

PROJECT SUMMARY Hematopoietic stem and progenitor cells (HSPCs) are characterized by their self-renewal and multipotent differentiation capacities. As such, they give rise to all mature blood cell types (e.g., myeloid, lymphoid, and erythroid) to maintain life-long hematopoiesis. Their regenerative capacity makes HSPCs valuable for cell replacement therapies in patients with hematological diseases, including those that are secondary to chemotherapy and radiotherapy. Understanding HSPC properties of self-renewal and multipotency allows for the development of methods to improve and maximize their therapeutic potential. By studying the embryonic origins of HSPC self-renewal and differentiation capacities, we aim to advance what is known about these defining characteristics of stem cells. In addition to HSPCs, other multi-lineage progenitors are produced during embryogenesis. These are limited in their self-renewal and differentiation output and are mostly regarded as transient in nature. These progenitor populations share many features of stem cells, confounding studies of HSPC properties within their native embryonic environments. Several studies in murine and zebrafish models suggest that these embryonic progenitors, and not HSPCs, are the dominant population generating mature blood cells in the embryo. If HSPCs are not necessary to sustain the embryo, what is their function during development? To answer this question, we propose to use zebrafish to determine when and where during development HSPCs self-renew and contribute to mature blood cell output in myeloid, lymphoid, and erythroid lineages. We will use novel regeneration and transplantation assays (Aim 1) to study self- renewal and lineage-tracing experiments (Aim 2) to investigate HSPC differentiation. Understanding how these properties are established and maintained is critical to harnessing stem cells for regenerative medicine.