Wednesday, February 5, 2025
2/5/2025
ABSTRACT Hematopoietic stem cells (HSCs) are rare cells that reside in the bone marrow (BM) where they are maintained by specialized microenvironments (termed niches) in which endothelial, stromal, and other hematopoietic cells synthesize important niche factors that regulate HSC function. Mesenchymal stem cells (MSCs) are an essential component of the BM niche. These rare non-hematopoietic perivascular stromal cells are characterized by their unique ability to self-renew and differentiate into bone, cartilage, and fat, ensuring proper skeletal development and maintenance. BM MSCs form specialized niches that regulate HSC function by secreting high levels of niche factors such as CXC-chemokine ligand 12 (CXCL12), stem cell factor (SCF), and Vascular Cell Adhesion Molecule-1 (VCAM1). VCAM1 is classically expressed on endothelial and stromal cells where it acts as an adhesion molecule that preferentially binds to α4β1 integrin on HSCs and progenitors. Deletion of Vcam1 in endothelial and hematopoietic cells induces HSC and progenitor cell (HSPC) mobilization into the peripheral blood without affecting endothelial cell (EC) homeostasis. However, while the contribution of endothelial-derived VCAM1 to BM homeostasis has been extensively studied, the specific role of MSC-derived VCAM1 on HSC and on MSC maintenance and multilineage potency remains unknown. Our supporting data indicates that MSCs are the BM’s main source of Vcam1 and suggests that VCAM1 is critical for the maintenance, survival, and function of MSCs. Since MSCs are important regulators of HSC function and essential for skeleton and BM stroma formation and maintenance, it is critical to understand the extent at which MSC-derived Vcam1 deletion impacts MSCs and hematopoietic homeostasis. Based on our supporting data, I hypothesize that MSC-derived VCAM1 expression is critical for MSC maintenance and niche functions. The overall aims of this project are to elucidate the mechanisms by which VCAM1 promotes MSC survival and regulates HSPC function. Altogether, our proposal will provide mechanistic evidence for VCAM1 as a novel regulator of MSCs. While the critical regulators of HSC maintenance and differentiation have been intensively studied, that of BM niche MSCs still remain largely unknown. Our studies will not only aid in our understanding of MSCs but also the mechanisms encompassing HSC maintenance to ultimately help improve treatments for hematopoietic diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).