Local and systemic regulation of hematopoietic stem cells by thrombopoietin

项目总结： 造血干细胞(HSCs)是一种关键且罕见的细胞群，能够自我 广泛更新并产生所有血细胞谱系。维护和维护HSC 在一生中都受外在调节；破坏这种调节可能会导致 HSCs丢失和造血功能衰竭。因此，了解HSC的外在调节 机制具有重要的治疗意义。血小板生成素(TPO)是一种 通常被认为是巨核细胞驱动力的造血细胞因子 增殖和血小板生成，但也被证明是HSC所必需的 维修。然而，由于TPO是在骨髓、肝脏和其他组织中产生的 组织中，局部和全身TPO对HSC功能的相对贡献仍然是 未知。本项目旨在通过使用TPO来表征TPO在HSC生物学中的活体作用 两种新的小鼠模型，可以识别骨骼中的TPO+群体 骨髓，以及有条件地从选定的组织中删除TPO。这里面的实验 该提案将定义TPO在HSC生物学中的作用，并对 利用我们对HSC调节方式的新理解进行临床治疗 在局部因素和系统因素之间取得平衡。

Project Summary: Hematopoietic stem cells (HSCs) are a critical and rare population of cells that can self- renew extensively and produce all blood cell lineages. HSCs are maintained and regulated throughout life by extrinsic regulation; disruption of this regulation can lead to loss of HSCs and hematopoietic failure. Thus, understanding HSC extrinsic regulatory mechanisms has important therapeutic implications. Thrombopoietin (TPO) is a hematopoietic cytokine that is canonically understood as a driver of megakaryocyte proliferation and platelet production, but has also been shown to be required for HSC maintenance. However, since TPO is made in the bone marrow, the liver and other tissues, the relative contributions of local and systemic TPO to HSC function are still unknown. This project aims to characterize the in vivo role of TPO in HSC biology by use of two novel mouse models that allow identification of TPO+ populations in the bone marrow, and conditional deletion of Tpo from select tissues. The experiments in this proposal will define the role of TPO in HSC biology, and have major implications for clinical therapies that take advantage of our novel understanding of how HSC regulation is balanced between local and systemic factors.