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Clonal analysis of hematopoietic stem and progenitor biology in situ

造血干细胞和祖细胞生物学原位克隆分析

基本信息

批准号：
9225236
负责人：
Fernando Camargo
金额：
$ 52.43万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9225236
关键词：
Address Adult Affect Aging Aging-Related Process Automobile Driving Behavior Biological Assay Biology Blood Blood Cells Bone Marrow Cell Compartmentation Cell physiology Cells Cellular biology Characteristics Cyclophosphamide Data Disease Elderly Emergency Situation Fluorouracil Genetic Goals Granulocyte-Macrophage Colony-Stimulating Factor Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic System Hematopoietic stem cells Human Impairment In Situ Infection Injury Knowledge Label Laboratories Lead Life Measurement Measures Modeling Mus Natural regeneration Nature Organism Outcome Study Phenotype Population Process Production Property Recruitment Activity Stem cells Stress System Technology Testing Time Transplantation Work base bone marrow failure syndrome exhaust experimental study injury and repair insight novel progenitor public health relevance self-renewal stem

项目摘要

DESCRIPTION (provided by applicant): Current dogma suggests that all hematolymphoid lineages are derived from a common ancestor, the hematopoietic stem cell (HSC). HSCs are believed to be the only cells with long-term self-renewal capacity in the bone marrow (BM), and are generally regarded as the cell of origin for continuous multi-lineage blood production during adult life. Evidence supporting this HSC-centric paradigm has been acquired through decades of work based largely on the use of functional assays involving transplantation. However, it is unclear to what extent functional characteristics of cells assayed under transplantation conditions are shared with cells driving non-transplant native hematopoiesis. Because of a historical lack of tractable systems, the mechanistic nature of non-transplant blood production has remained largely unexplored. To address this limitation, my laboratory has developed a novel experimental system in mice where cells can be uniquely and genetically labeled in situ. Using this system, clonal fate of multiple hematopoietic populations can be tracked over time and across lineages, for the first time, in a native context. Our preliminary findings with this model have revealed surprisingly unique features of unperturbed hematopoiesis. Among other things, our data demonstrate that long-term native hematopoiesis is mainly driven by waves of progenitor recruitment and that HSC contribution during this process is minimal. Thus, we hypothesize that native hematopoiesis is driven by fundamentally different mechanisms as transplantation. In this proposal, we aim to extend our earlier findings and to provide comprehensive insight into the biology of blood production in situ. Specifically, we will test whether HSCs can be recruited into productive hematopoiesis via injury, stress, or infection. We will also test whether progenitor recruitment can exhaust during the aging process. Additionally, we will revisit the existence of classical progenitor populations and lineage relationships using our clonal strategy. Completion of this project would elucidate the basic mechanisms underlying blood production and provide insight into stem cell dynamics during disease processes.