Stem Cell Self-Renewal
We study the cell-intrinsic and cell-extrinsic mechanisms that regulate stem cell self-renewal and the roles these mechanisms play in tissue homeostasis and cancer. The maintenance of many adult tissues depends on the persistence of stem cells throughout life. Stem cells are maintained in adult tissues by self-renewal, the process by which stem cells divide to make more stem cells. By better understanding this process, we gain insights into how tissues develop and regenerate, how reduced self-renewal can lead to degenerative disease, and how increased self-renewal can lead to tumorigenesis. We identified a series of mechanisms that distinguish stem cell self-renewal from restricted progenitor proliferation as well as self-renewal mechanisms that are conserved among stem cells in different tissues. We are currently focused on areas of cellular physiology that are understudied in stem cells, including metabolism and proteostasis.
We focus on hematopoietic stem cells (HSCs) and the specialized microenvironments, or niches, in which they reside. We identified the location and cellular composition of the HSC niche in bone marrow, including the Leptin Receptor-expressing (LepR+) stromal cells that are the major source of factors for HSC maintenance. These LepR+ cells also include the skeletal stem cells that are the main source of new osteoblasts and adipocytes in adult bone marrow. We discovered a new bone-forming growth factor, Osteolecin, that is produced by the LepR+ cells and that promotes the maintenance and repair of the adult skeleton. LepR+ cells also give rise to osteogenic and adipogenic progenitors that create niches for hematopoietic stem and progenitor cells. We also identified the HSC niche for extramedullary hematopoiesis in the spleen that is activated when the bone marrow is damaged by chemotherapy, radiation, or cancer. This is an exciting time in niche biology as we now have the possibility of going beyond growth factors to ask what other mechanisms niches use to regulate stem and progenitor cell function. Recent studies from our lab have identified metabolic and mechanical regulation.