Department: Medical Biophysics, University of Toronto
Lineage specific differentiation of embryonic stem cells
The overall goals of my research program are to understand the mechanisms that control mesoderm and endoderm induction and specification in mouse and human embryonic stem (ES) cell cultures. Our studies focus specifically on the generation of the following derivative lineages: hematopoietic, vascular, cardiac, hepatic and pancreatic. Research projects in these areas include: 1) characterization of the earliest developmental stages of lineage commitment, 2) identification of the signaling pathways regulating lineage specification and maturation and 3) generation of functional cell populations for transplantation in preclinical models of human disease. For the mesoderm-derived lineages we have demonstrated that the earliest stages of hematopoietic and cardiac development in ES cell cultures are defined by the appearance of progenitors that display both tissue specific and vascular potential. Within the hematopoietic system, these progenitors are known as hemangioblasts whereas those that define the onset of cardiac development are known as cardiovascular progenitors. Our current studies are aimed at defining the mechanisms that control the proliferation and differentiation of these progenitor populations and on strategies to demonstrate their potential to function in vivo following transplantation into appropriate recipient animals. The long-term goal of these transplantation studies is to develop new therapies for the treatment of hematopoietic and cardiovascular diseases. With respect to endoderm derivatives, we have shown that the combination of activin A, BMP-4 and bFGF will lead to the efficient generation of cells with characteristics of immature hepatocytes. Modification of this induction protocol results in the development of pancreatic progenitors. Our current research projects in this area are focused on understanding the pathways that regulate the maturation of these populations into functional hepatocytes or insulin-secreting pancreatic beta cells. Access to ES cell-derived hepatocytes and beta cells will provide a novel source of these cells for cell based therapy approaches for the treatment of diabetes and certain types of liver disease.