Regulation of blood cell production by endothelial cell-derived retinoic acid receptor gamma

Summary We make billions of blood cells every day due to finely regulated processes involving intrinsic and extrinsic factors. We have shown that the vitamin A receptor, RARg, is a key regulator of blood cell production and this project will explore one of its key roles.

Project Details

We make billions of blood cells every day. In the adult, haematopoiesis [the ongoing formation of blood cells from haematopoietic stem cells (HSCs)] occurs via a tightly regulated process of HSC self-renewal vs differentiation to mature blood cells. Deregulation of HSCs can result in blood cell diseases (including cancers).

We have previously shown that vitamin A increases HSC self-renewal. We have also shown that mice lacking one of the vitamin A receptors, retinoic acid receptor gamma (RARg), have reduced numbers of HSCs and impaired haematopoiesis. However, these phenotypes have been shown to involve direct and indirect influences of RARg (via cells of the bone marrow microenvironment, which act as the factory where blood cells are produced).

We have deleted RARg in endothelial cells and these mice have a range of different blood cell phenotypes, including reduced platelets and red blood cells. The mice also have altered bone and blood vessel content. This project will identify if the HSCs are altered in the mice, and will also use an innovative imaging technology to identify how some of these blood cell phenotypes are occurring in response to the changes in the bone marrow microenvironment.

The studies will incorporate a range of different techniques used in HSC biology, including isolation of bone marrow cells from mice, HSC transplants, flow cytometry, fluorescence-based immunostaining of cell suspensions and tissue sections, and molecular biology techniques. The student will be trained in HSC biology, bone marrow microenvironment and stem cells, thus background knowledge in the subject is not required.