Statement of Benefit to California:
Year 1Human embryonic stem cells (ESCs) are self-renewing and pluripotent cells derived from the inner cell mass of the blastocyst. Human ESCs are an unlimited and widely applicable cell source for regenerative medicine, making them desirable candidates for cell replacement therapy. However, the use of human ESCs also carries the danger of possible uncontrollable cellular proliferation and differentiation, a serious problem that is as yet unresolved. This potentially serious complication may occur if the transplanted human ESCs take an inappropriate path such as teratoma formation. Broadly defined, teratomas are haphazard arrays of cell differentiation that appears to recapitulate the main events involved in early embryonic development, but in a disorganized manner. Teratomas have been observed to grow from both undifferentiated mouse ESCs and human ESCs. Thus, the ability to visualize cellular proliferation and differentiation in vivo would be an invaluable next step toward monitoring and controlling cellular misbehavior.
The three specific aims of the project are as follow:
Aim 1: To develop a novel imaging platform for tracking human ESCs in vivo
Aim 2: To monitor the tumorigenicity profiles of different human ESC lines
Aim 3: To examine key regulatory processes involved in human ESC differentiation into cardiac cells
For Aim 1, we have created 3 human ESC lines (H1, H7, and H9) that stably express fusion reporter genes. Using novel imaging technology, we have successfully tracked human ESC teratom formation de novo in living subjects (Cao F et al, Cancer Research 2009). For Aim 2, we have shown that a minimum of 1x10(5) human ESCs in the myocardium and a minimum of 1x10(4) cells in the skeletal muscle was necessary for teratoma development, suggesting that cell number does play a critical factor (Lee A et al, Cell Cycle 2009). For Aim 3, we have performed detailed transcriptional and functional profiling analysis of human ESC derived cardiomyocytes in mouse model of myocardial infarction (Cao F et al, PLoS ONE 2008). Lastly, we have shown that the STAT3 signaling pathway is critical for the development and differentiation of cardiac cells.
In summary, we have made significant progress in understanding the divergent biology of human ESC differentiation and tumorigenicity. Over the past 2 years, we have published 8 papers that were supported by the CIRM Seed Grant.