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

项目摘要 我们的长期研究目标是了解调节干细胞命运决定的机制。 在这里，我们建议通过调查胎儿造血的作用，调节和 造血干细胞（HSC）的新群体的特异性。虽然这个群体满足了 功能性HSC的最严格标准是，它们在正常发育期间的寿命仅限于 有限的发展窗口。不能持续到成年期的功能性HSC从未被发现。 之前观察到，因此定义了具有独特终点的确定性造血的新波。 我们发现这些新的HSC提供了一个独特的机会，以追求的机制，调节 干细胞在生命中的持久性。此外，特定阶段的HSC的存在将提供 了解在特定的发育时间点如何建立专门的免疫细胞， 满足免疫系统的不同需求。因为我们的发现是基于 基因缺失事件，我们的模型也独特地适合于理解细胞之间的关系 在HSC特化和分化过程中的种群。这些问题将 通过移植测定和体外实验的组合进行。结果将提供 关于建立血液和免疫系统的基本新见解指导战略， 对抗发育性造血障碍，包括某些类型的贫血，自身免疫性 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. .