Regulation of functionally discrete hematopietic stem cells

项目摘要 一旦胚胎和新生儿细胞快速扩增完成，造血干细胞（HSC） 从细胞周期，并作为一个水库，以维持生产的所有血细胞在整个成年生活。 HSC是功能异质性的，包含具有不同分化和持久植入的细胞 潜力然而，成年HSC的分子驱动因素仍然是个谜。我们开发了几种鼠标 模型和深层基因组学数据集支持离散HSC细胞状态的存在， 分子和功能上。此外，我们发现HSC的分裂历史可能解释了这些基因组学特征， 差异;将这些人口置于基于分区历史的等级结构中。此外，我们的数据 表明HSC在进入细胞周期后显著重塑线粒体网络， 线粒体在恢复静止后不恢复稳态。我们假设HSC是 在功能上不同的HSC状态中分层组织，并且这种组织可以通过其 线粒体提供记忆的分区历史。拟议的工作将首先深刻建立 离散HSC状态的分子结构，包括最具功能的群体的驱动程序，然后定义 线粒体在离散HSC群体的功能编程中的作用，包括 线粒体的维持会导致适应性下降。首要目标是定义单元状态 HSC及其衍生物遇到的问题，以及提供对潜在的 转录电路和细胞生物学变化指示状态之间的转换。我们预计 建议的研究，以促进造血系统的基本了解-信息 可用于开发HSC扩增的新模式，在BMT之前验证移植物，或安全地 基因操作HSC用于基因治疗。

PROJECT SUMMARY Once rapid embryonic and neonatal cellular expansion is completed, hematopoietic stem cells (HSC) withdraw from the cell cycle, and serve as a reservoir to sustain the production of all blood cells throughout adult life. HSCs are functionally heterogenous and contain cells with disparate differentiation and durable engraftment potential. However, molecular drivers of adult HSC remain enigmatic. We have developed several mouse models and deep genomics data sets which support the existence of discrete HSC cell states that differ both molecularly and functionally. Moreover, we find that HSC history of division may account for these genomic differences; placing these populations in a hierarchical structure based on divisional history. Further, our data suggest that HSC dramatically remodel the mitochondrial network upon entry into cell cycle and that mitochondria do not return to a homeostatic state after returning to quiescence. We hypothesize that HSC are hierarchically organized in functionally distinct HSC states, and that this organization can be resolved by their divisional history for which mitochondria provide memory. The proposed work will first incisively establish the molecular architecture of discrete HSC states, including drivers of the most functional population, then define the role of mitochondria in functional programming of discrete HSC populations, including how alterations in mitochondria maintenance contribute to a decline in fitness. The overarching goal is to define the cell states encountered by HSC and their derivatives, as well as to provide mechanistic insight into the underlying transcriptional circuits and cell biological changes indicative of transition between states. We expect the proposed research to contribute to a fundamental understanding of the hematopoietic system – information that can be used to develop new modalities for HSC expansion, validate grafts before BMT, or safely genetically manipulate HSC for gene therapy.