MEIS1: At the Crossroads Between Metabolic and Cell Cycle Regulation

Stem cells undergo self-renewal, maintaining themselves in an undifferentiated state while generating differentiated cells that are required for the tissue homeostasis or repair. One intriguing feature of stem cells is their maintenance in their respective hypoxic niche. Survival in this low-oxygen microenvironment requires significant metabolic adaptation. However, little is known about stem cell metabolism, its regulation or its effect on stem cell function. We started our work by focusing on the most comprehensively characterized adult stem cell population, the hematopoietic stem cells (HSCs). We demonstrate that mouse and human HSCs utilize glycolysis instead of mitochondrial oxidative phosphorylation to meet their energy demands. Furthermore, we demonstrate that Meis1 and Hif-1α are markedly enriched in HSCs and that Meis1 functions upstream of the two master redox regulators Hif-1α and Hif-2α, where loss of Meis1 results in a metabolic shift from glycolysis to mitochondrial oxidative metabolism, and increased oxidative stress, and loss of HSC quiescence. These results underscore the critical link between metabolism and cell cycle regulation of HSCs. We then sought to determine whether other stem cell populations share these unique metabolic characteristics. This strategy enabled us to identify the epicardium and the subepicardium of the heart as the cardiac hypoxic stem cell niche, which houses a metabolically distinct, Hif-1α positive population of glycolytic cardiac progenitors. Moreover, our studies indicate that Meis1, which regulates HSC metabolism and quiescence, also induces post-natal cell cycle exit and quiescence of cardiomyocytes through induction of synergistic cyclin dependent kinase inhibitor families. We demonstrate that both embryonic and adult deletion of Meis1 in cardiomyocytes results in widespread cardiomyocyte proliferation in the adult heart. Overall, our studies identify Meis1 as a critical transcriptional regulator of cell cycle and metabolism.