Regulation of Bone Marrow Hematopoietic Stem Cell Niches
Date of Award
Doctor of Philosophy (PhD)
In adult mammals, Hematopoietic stem cells (HSCs) depend on specialized bone marrow (BM) HSC niches for quiescence, proliferation, self-renewal, and differentiation. HSC niches are predominantly composed of non-hematopoietic cells, including perivascular mesenchymal stem and progenitor cells (MSPCs) and endothelial cells (ECs). Although historically defined as HSC niches, more recent studies demonstrated that these niches are also critical for the development and maintenance of hematopoietic progenitors and differentiated hematopoietic cells. Importantly, some terminally differentiated hematopoietic cells such as macrophages, megakaryocytes, and regulatory T cells can in turn relay signals back to the HSC or alter the HSC niche, and control the size of the HSC compartment under homeostatic conditions. While whether early hematopoietic progenitors are involved in the regulation of HSC and HSC niche homeostasis is still unclear. Moreover, while certain hematopoietic cytokines produced by MSPCs and ECs act in cell lineage-restricted manners, other factors such as SCF are shared by multiple hematopoietic cell subsets. Whether hematopoietic stem and progenitor cells compete for niche resources is not entirely clear. In this study, we studied these questions by examining the impact of CXCR4 conditional deletion at multiple stages of hematopoietic cell development. We found that when multipotent progenitors are deficient in CXCR4, the HSC compartment size increase by about two-fold, without any measurable loss of fitness. This increase occurred without any major change in the transcriptome or transcriptional heterogeneity of the HSC niche compartment. Surprisingly, HSC expansion was entirely controlled by the availability of membrane-bound SCF on niche cells, which is rapidly consumed by c-Kit-expressing hematopoietic progenitor cells under steady-state. These studies provide new insights into the fine-balance between HSCs and downstream progenitors regulated by a poorly understood phenomenon of cellular competition in the hematopoietic organ.
Miao, Runfeng, "Regulation of Bone Marrow Hematopoietic Stem Cell Niches" (2021). Yale Graduate School of Arts and Sciences Dissertations. 163.