Regulation of functionally discrete hematopietic stem cells

项目总结 一旦胚胎和新生儿细胞完成快速扩增，造血干细胞(HSC)就会退出 从细胞周期中分离出来，作为一个储存库，在整个成年生活中维持所有血细胞的生产。 造血干细胞在功能上是异种的，包含分化不同的细胞和持久的植入 潜力。然而，成人HSC的分子驱动因素仍然是个谜。我们已经研制出几只老鼠。 支持存在离散的HSC细胞状态的模型和深度基因组数据集 从分子和功能上讲。此外，我们发现HSC的分裂历史可能解释了这些基因组 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 提示HSC在进入细胞周期后极大地重塑线粒体网络 线粒体在回到静止状态后不会恢复到平衡状态。我们假设HSC是 在功能上不同的HSC状态中分层组织，并且这个组织可以通过他们的 线粒体为其提供记忆的分区历史。拟议的工作将首先深刻地确立 离散的HSC状态的分子结构，包括最功能群体的驱动因素，然后定义 线粒体在离散的HSC群体功能编程中的作用，包括如何改变 线粒体的维护会导致健康状况的下降。首要目标是定义单元状态 HSC及其衍生产品所遇到的问题，以及提供对潜在 转录回路和细胞生物学变化指示状态之间的转换。我们期待着 建议的研究有助于从根本上了解造血系统--信息 这可用于开发新的HSC扩增模式，在BMT之前验证移植物，或安全地 通过基因操作HSC进行基因治疗。

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.