The expectations for stem cell transplantation to treat diseases have been high. However, accumulating evidence indicates that stem cell homing is a very tough issue, and stem cell transplantation seems to result in a majority of “homeless stem cells”. Stem cells’ innate ability to travel to the right place in the body is very limited. Only a very small fraction of cell grafts will dock properly. The rest will be eliminated by apoptosis or become problematic. On the other hand, human embryonic stem cells (hESCs) are notoriously difficult to maintain due to spontaneous differentiation and apoptosis within culture. Understanding mechanisms that regulate hESC self-renewal, differentiation, and apoptosis will enhance our ability to manipulate hESCs and to realize their potential for regenerative medicine. Previous studies on the regulation of stem cell behavior have focused largely, if not exclusively, on the role of nuclear genes. The present proposal seeks to expand this existing paradigm. We hypothesize that mitochondria play a critical role in determining stem cell fate. We propose to determine the role of mitochondria in the regulation of hESC behavior with a combination of cellular and molecular techniques to provide overlapping approaches to unravel novel mechanisms controlling hECs survival, self-renewal and differentiation. We will test whether the mitochondrial fusion and fission machinery regulates mitochondrial morphology and redox state, and thus play important roles in hESc fate choices. This proposal will reveal important mitochondrial signaling pathways in regulating hESCs. The information will expand our ability to manipulate hESCs, with the ultimate goal of designing efficient hESC-based therapies.
The state of California is a pioneer in supporting critically important stem cell research. Our research will enhance our ability to propagate and culture these cells and advance our understanding of the mechanisms that mediate stem cell development and differentiation. This work will provide new insights into mitochondrial mechanisms that regulate hESCs and potential strategies for treating mitochondrial diseases that may directly affect Californians suffering from such diseases, for which there currently is no cure.