Regulation of functionally discrete hematopietic stem cells

功能离散造血干细胞的调节

基本信息

批准号：
10544722
负责人：
Marie-Dominique Filippi
金额：
$ 57.45万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-12 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544722
关键词：
ATAC-seq Adult Affect Architecture Biological Biological Assay Blood Cells Cell Cycle Cell Separation Cell division Cell fusion Cells Clinical Coupled Data Data Set Disparate Embryo Endowment Engraftment Epigenetic Process Exercise Failure Family Frequencies GFI1 gene Gene Expression Genes Genetic Genetic Transcription Genomics Goals Hematopoietic System Hematopoietic stem cells Impairment Investments KDM5B gene Label Lead Life Maintenance Maps Marrow Mediating Memory Mitochondria Modality Modeling Molecular Mus Myelogenous Neonatal Population Production Proliferating Proteins Recording of previous events Regulation Research Resolution Role Specific qualifier value Stress Structure System Transgenic Organisms Transplantation Work analytical tool cell growth fitness functional decline functional loss gene regulatory network genetic manipulation genomic data hematopoietic stem cell expansion hematopoietic stem cell quiescence in vivo insight mouse model network models novel pharmacologic progenitor programs regeneration potential replication stress single cell analysis single-cell RNA sequencing stem cell division stem cell function stem cell gene therapy stem cell population stem cells transcription factor

项目摘要

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.

项目摘要一旦快速胚胎和新生儿细胞膨胀完成，造血干细胞（HSC）退出从细胞周期开始，并作为在成年生活中维持所有血细胞生产的储层。 HSC在功能上是异质的，包含具有不同分化和耐用植入的细胞潜在的。但是，成人HSC的分子驱动因素仍然神秘。我们已经开发了几只鼠标模型和深基因组学数据集，这些数据集支持存在不同的HSC细胞的存在，两者都不同分子和功能。此外，我们发现HSC的分裂历史可能解释了这些基因组差异；将这些人群置于基于部门历史的层次结构中。此外，我们的数据建议HSC进入细胞周期后，动态重塑线粒体网络，并且线粒体恢复静止后不会恢复稳态状态。我们假设HSC是在功能上不同的HSC状态下层次组织，并且该组织可以通过其解决方案来解决线粒体提供记忆的部门历史。拟议的工作将首先建立离散HSC状态的分子体系结构，包括功能最强的驱动因素，然后定义线粒体在离散HSC种群功能编程中的作用，包括如何改变线粒体维护有助于健身的下降。总体目标是定义单元格状态 HSC及其衍生物遇到的，并提供机械洞察力转录电路和细胞生物学变化表示状态之间过渡。我们期望拟议的研究是为了有助于对造血系统的基本理解 - 信息可以用来开发用于HSC扩展的新方式，在BMT之前验证移植物或安全基因治疗的基因操纵HSC。