Role and Regulation of a Novel, Developmentally Restricted Hematopoietic Stem Cel

项目总结 我们的长期研究目标是了解调控干细胞命运决定的机制。 在这里，我们建议通过研究胎儿造血的作用、调节和 一种新的造血干细胞(HSC)群体的特征。尽管这一人口符合 对于功能性HSC最严格的标准是，它们在正常发育期间的寿命被限制在 有限的发展窗口。功能正常的HSC不会持续到成年，从来没有 之前观察到的，因此定义了具有明显终点的新的终止性造血波。 我们对这些新的HSC的发现为我们提供了一个独特的机会来探索调节 干细胞在生命中的持久性。此外，阶段特定的HSC的存在将提供 对在特定发育时间点如何建立专门的免疫细胞的见解 满足对免疫系统的不同要求。因为我们的发现是基于不可逆转的 基因缺失事件，我们的模型也非常适合于理解细胞之间的关系 HSC特化期间的种群和发育过程中的分化。这些问题将是 通过移植试验和体外实验相结合的方法进行研究。结果将提供 关于建立血液和免疫系统指导战略的基本新见解 抗击发育性造血疾病，包括某些类型的贫血、自身免疫 疾病和儿童癌症。 。

PROJECT SUMMARY Our long-term research goals are to understand the mechanisms that regulate stem cell fate decisions. Here, we propose to pursue questions in fetal hematopoiesis by investigating the role, regulation and specification of a novel population of hematopoietic stem cells (HSC). Although this population fulfills the most stringent criteria for functional HSC, their life-span during normal development is restricted to a limited developmental window. A functional HSC that does not persist into adulthood has never been observed before and therefore defines a novel wave of definitive hematopoiesis with a distinct endpoint. Our discovery of these novel HSC provides a unique opportunity to pursue the mechanisms that regulate the persistence of stem cells throughout life. In addition, the existence of stage-specific HSC will provide insights to how specialized immune cells are established during specific developmental timepoints to meet the varying demands on the immune system. Because our finding is based on an irreversible genetic deletion event, our model is also uniquely suited for understanding the relationship between cell populations during HSC specification and differentiation during development. These questions will be pursued by a combination of transplantation assays and in vitro experiments. The outcomes will provide essential new insights on the establishment of the blood and immune system guide strategies for combatting developmental hematopoietic disorders, including certain types of anemia, autoimmune disease, and childhood cancer. .