Mitochondrial dynamics and quality control in hPSC self renewal and differentiation
Understanding fundamental aspects of stem cell biology is essential to develop regenerative medicine therapies. Unacceptable outcomes include inadequate functionality, exhaustion, immune rejection, cancer development, and others. Our studies strongly support our core hypothesis that mitochondrial function determines stem cell quality and safety. Dysfunctional mitochondria foster cancer, diabetes, obesity, neurodegeneration, immunodeficiency, and cardiomyopathy. Unlike whole genome approaches, methodological hurdles for evaluating mitochondria in human embryonic stem cells (hESCs) and in reprogrammed human induced pluripotent stem cells (hiPSCs) are significant and techniques developed or adapted for stem cells are almost non-existent. With a CIRM-supported grant, we developed new approaches for analyzing respiration in hESCs. We also describe the function of stem cell mitochondria in low oxygen (hypoxia), in normoxia (room air), and during differentiation. The mitochondrial network structure changes between fragmented and fused appearances with differentiation or reprogramming, and that a mitochondrial quality control system is activated as hESCs differentiate. Our studies are providing new basic and clinical insights into stem cell biology and hold promise for developing applications to common diseases, such as Parkinson and Alzheimer neurodegenerative disorders and cancer. These CIRM-supported advances provide the underpinnings for our current proposal.
Our proposal benefits California by adding new essential knowledge on mitochondrial mechanisms that control human pluripotent stem cell (hPSC) fate and function to support the taxpayers' commitment to personalized cell therapies. This work builds on highly successful 2-year CIRM Seed and 3-year Basic Biology I awards. CIRM funds to date resulted in 20+ published studies, numerous conference presentations, and the training of 14 individuals including post-docs, graduate students, undergraduates, and CIRM Bridges to Stem Cell Biology program trainees, some of whom have now entered the California workforce. Those studies provided the first methods and thorough characterizations of the function of mitochondria in stem and differentiated cells. This new CIRM BBV proposal is groundbreaking for revealing how mitochondrial quality control and dynamics layered with epigenetic mechanisms drive hPSC differentiation, which has implications for regenerative medicine. Our ongoing work underpins therapy development in California’s major academic centers and will provide data for many of California's biotechnology companies in the growing stem cell industry, whose success will propel hiring and increased economic prosperity for the state. With success, tangible health and economic impact on California, its academic institutions and companies, and the rest of the nation will be achieved as California leads the way forward with personalized medicine for the 21st century and beyond.