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

描述（由申请人提供）：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，我们建议通过研究一种新的造血干细胞（HSC）群体的作用、调节和规范来探讨胎儿造血中的问题。尽管这一人群符合功能性HSC的最严格标准，但他们在正常发育期间的寿命仅限于有限的发育窗口期。以前从未观察到功能性HSC不能持续到成年期，因此定义了一种具有明确终点的新型造血浪潮。我们对这些新型HSC的发现提供了一个独特的机会来探索调节干细胞在整个生命过程中的持久性的机制。此外，阶段特异性HSC的存在将为在特定的发育时间点如何建立特异性免疫细胞以满足对免疫系统的不同需求提供见解。因为我们的发现是基于不可逆的基因缺失事件，我们的模型也非常适合于理解HSC规范过程中细胞群与发育过程中分化之间的关系。这些问题将通过移植分析和体外实验的结合来解决。这些结果将为血液和免疫系统指导策略的建立提供重要的新见解，以对抗发育性造血疾病，包括某些类型的贫血，自身免疫性疾病和儿童癌症。

DESCRIPTION (provided by applicant): 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 fo 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 time points 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. .