Year 1

Our project strives to understanding how changes in the health of the stem cell proteome, or its proteostasis, affect the physiology, mortality, and pluripotency of these unique cells. Previously, we discovered that stem cells exhibited a heightened state of proteostasis, as seen by dramatic increases in their capacity to degrade unwanted proteins. Human embryonic stem cells (hESCs) thus displayed a remarkable capacity to maintain their proteomes that was rapidly lost during differentiation. Subsequently, through the support of CIRM, we have embarked on an ambitious undertaking to understand how other subcellular pathways responsible for maintaining proteostasis play a role in stem cell health.

This year we are pleased to report progress on multiple fronts toward this end. We have found evidence for an important role of subcellular organelles in maintaining stem cell health. We have found a heightened sensitivity of these cells to specific stressors. We have made considerable progress in the establishment of endogenous fluorescent reporter lines such that we can monitor stress responses in hESCs in vivo. We have tested the effect of activation of a wide variety of stress response pathways on induced pluripotent stem cell (iPSC) reprogramming efficiency. Collectively, these results promise exciting, mechanistic gains toward an understanding of basic stem cell biology.