Autophagy regulation of stressed haematopoiesis

The ability of haematopoietic stem cells (HSC) to expand and differentiate is key to normal homeostasis and the systemic immune response.
HSCs promote a rapid immune response by generating innate and adaptive immune cells that are recruited to the site of infection. After the infection has been overcome HSC numbers decline to pre-infection levels, however what controls this reduction in numbers is not known. Our laboratory has shown that the non-haematopoietic cells (fibroblasts and adipocytes) support HSC maintenance in the bone marrow (BM) microenvironment. Others have shown that BM macrophages also support HSC expansion. However, the primary function of macrophages is phagocytosis (to engulf other cells, debris or microbes). Recently, a pathway called LC3-associated phagocytosis (LAP), which combines features of autophagy with phagocytosis, has been shown to be important in clearing cell debris.
The project will hypothesise that LAP controls the reduction of HSC and progenitor cells in the BM after infection and that deficiencies in LAP allow for a dysfunctional HSC phenotype. The project aims to study the role of macrophage LAP on regulating the HSC pool in the BM microenvironment in response to infection and whether defective LAP leads to a dysfunctional immune response.