The bone marrow (BM) microenvironment is a complex multicellular system comprised of specialized niche cells that regulate the maintenance of the hematopoietic stem cell (HSC) pool through the production of pro-hematopoietic factors. Crosstalk between various niche cells coordinates the differentiation, maintenance, and regeneration of HSCs. However, the precise mechanism by which niche cells communicate with the HSCs and their progeny to reconstitute hematopoiesis is unknown. Our group has previously demonstrated that Akt-activated endothelial cells are indispensable for the regeneration of the Notch-dependent HSC pool. Our laboratory is currently defining the role of endothelial cells in the following projects:
Activation state of the BM vascular niche regulates hematopoiesis after myelosuppressive therapy: Disruption of BM homeostasis during chemo/radiotherapy can result in prolonged damage to the BM microenvironment, hindering its ability to re-establish functional hematopoiesis. The long-term goal of this project is to improve cytopenias associated with BM failure by rejuvenating the BM microenvironment to promote hematopoietic regeneration and to reduce the morbidity and mortality of these disorders. The objective will be to determine how the activation state of BM endothelial cells regulates the HSC pool during recovery from ionizing radiation and/or toxin-induced bone marrow injury.
Aged vascular niches alter HSC function: Age-related changes in the hematopoietic system include compromised adaptive immune function and an increase in the frequency of myeloid malignancies. While inherent autonomous changes in the aged HSC compartment have been widely accepted, the genesis of these changes remains a black box. The overarching goal of this research proposal is to better understand how aging alters the BM vascular niche, thereby altering its capacity to support functional hematopoiesis. By defining the role of endothelial cells in hematopoiesis in a physiologically-relevant setting such as aging, we will begin to dissect the mechanisms by which the BM vascular niche regulates the highly controlled balance between HSC self-renewal and differentiation.
Rejuvenation of vascular niches to treat age-related hematopoietic malignancies: The long-term objective of this project is to define the mechanisms by which dysregulation in the aged BM vascular niche leads to the initiation and progression of age-associated acute myeloid leukemia. Our group is interested in determining how aging of the BM vascular niche results in an increase of pro-leukemic angiocrine factors at the expense of normal hematopoiesis, and how alterations in signaling pathways within the BM vascular niche ultimately lead to the initiation and/or progression of hematopoietic maliganancies.