Mitochondria are known as the powerhouse of cells, generating energy (ATP) to power the biochemical processes of life. What is less well appreciated is that small organic molecules generated within mitochondria, called metabolites, traffic into the cell cytoplasm and nucleus where they act as essential cofactors for enzymes that regulate cell function. Leading cancer researchers worldwide now recognize how important changes in metabolites are for causing changes in the activities of enzymes that control gene expression, leading to cancer. Because cancers are biochemically abnormal, questions about how metabolites control cell differentiation cannot be easily addressed in the setting of cancer. It turns out that the ideal experimental system for this question is human pluripotent stem cells (hPSCs) and their differentiation into mature cell lineages. With two prior rounds of funding from CIRM, we determined that a metabolism gene, UCP2, regulates hPSC differentiation without knowing the mechanism. Since UCP2 regulates the manufacture of metabolites in mitochondria, we suspect this is a fundamental, key mechanism for regulating hPSC differentiation. Given our past productivity and success in this general area with 18+ publications using CIRM funds, we are uniquely positioned to determine how metabolism directly controls the genes that regulate hPSC self-renewal and differentiation potential, which has important implications for the field of regenerative medicine going forward.
Our proposal benefits California by adding new essential knowledge on metabolic 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 18+ 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 BBIV proposal is groundbreaking for revealing how metabolism regulates changes in gene expression to 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 and pharmaceutical companies in the ever 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 and its people lead the way forward with personalized medicine for the 21st century and beyond.