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：
10319603
负责人：
Marie-Dominique Filippi
金额：
$ 57.97万
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/10319603
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 Distributional Activity Embryo 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 Molecular Myelogenous Neonatal Pharmacology Population Production Proteins Recording of previous events Regulation Research Resolution Role Stress Structure System Transgenic Organisms Transplantation Work analytical tool base cell growth fitness functional decline functional genomics gene regulatory network genetic manipulation genomic data hematopoietic stem cell expansion hematopoietic stem cell quiescence in vivo insight loss of function mouse model network models novel 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.

项目概要一旦胚胎和新生儿细胞快速扩增完成，造血干细胞 (HSC) 就会被撤回来自细胞周期，并作为维持整个成年生命中所有血细胞产生的水库。 HSC 具有功能异质性，包含具有不同分化和持久植入的细胞然而，成人 HSC 的分子驱动因素仍然是个谜。模型和深度基因组学数据集支持存在两种不同的离散 HSC 细胞状态此外，我们发现HSC的分裂历史可能解释了这些基因组。差异；根据划分历史将这些人群置于分层结构中。表明 HSC 在进入细胞周期后会显着重塑线粒体网络，并且线粒体在恢复静止后不会恢复稳态。我们勇敢地说 HSC 是这样的。在功能不同的 HSC 状态中按等级组织，并且该组织可以通过它们来解决拟议的工作将首先深入地建立线粒体提供记忆的分裂历史。离散 HSC 状态的分子结构，包括最具功能性群体的驱动因素，然后定义线粒体在离散 HSC 群体功能编程中的作用，包括线粒体如何改变线粒体维护会导致健康状况下降，首要目标是定义细胞状态。 HSC 及其衍生品遇到的问题，以及提供对底层的机制洞察转录回路和细胞生物学变化表明状态之间的转变。拟议的研究有助于对造血系统的基本了解 - 信息可用于开发 HSC 扩增的新方式、在 BMT 之前验证移植物或安全地用于基因治疗的基因操作HSC。