Energy Metabolism in Human Pluripotent Stem Cells.

摘要

Human pluripotent stem cells (hPSC) including embryonic stem cells (hESC) and induced plutipotent stem cells (hIPSC) are pluripotent cells that can differentiate into all lineages of tissues, and have great potential as a tool for regenerative medicine. Intensive studies have been performed to study the underlying mechanisms that define a pluripotent cell state or a differentiated cell state, and the processes involved in the transition between these two states, and most of these studies focused on gene regulations by transcription factors or epigenetic regulations. However, another intriguing difference between pluripotent cells and differentiated cells-metabolism, has yet been well studied, and could also be an important component of the "stemness" supporting stem cell growth, proliferation and differentiation. We developed a series of bioenergetic measurement methods to thoroughly characterize hPSC metabolic functions. We found that hPSCs rely more on glycolysis in producing ATP in comparison to differentiated cells, and their mitochondria are functional and they respire with maximum capacity but are partially uncoupled for making ATP. Mitochondiral Uncoupling protein 2 (UCP2) plays a regulatory role in hPSC energy metabolism by preventing mitochondrial glucose oxidation and facilitating glycolysis via substrate shunting. With early differentiation, hPSC proliferation slows, energy metabolism decreases, and UCP2 is repressed, resulting in decreased glycolysis and maintained or increased mitochondria! glucose oxidation. Ectopic UCP2 expression perturbs this metabolic transition and impairs hPSC differentiation.;Our studies showed hESCs and hIPSCs share very similar metabolic functions. However, careful analysis of gene expression, epigenetic status and copy number variations indicates they can be distinguished by unique genetic or epigenetic signatures, especially for hIPSC in early passages after transduction. After culture expansion, they will be selected and resemble hESC more. These studies demonstrate it is essential to characterize the genetic, epigenetic and even metabolic features of newly derived hIPSC for the safety of applying hPSCs for regenerative medicine.;Another interesting difference between these two types of pluripotent cells is that hESCs, but not hPSCs, are derived from inner cell mass of blastocysts which are exposed to a hypoxic environment. It has been suggested low O 2 tension affects stem cell self-renewal and differentiation. We studied the Hypoxia-inducible factor alpha, a main hypoxia response regulator, and found an unexpected role of it in regulating stem cell differentiation.