Modularity in Somatic Cell Reprogramming

Reprogramming relies on the concept that cellular fate is plastic, and therefore a considerable effort has been made to develop molecular strategies that reset the epigenome to achieve distinct cell fates, including stem cells. Deriving induced pluripotent stem (iPS) cells has thus emerged as a critical approach in personalized regenerative medicine that provides an exclusive platform to study human development ex utero, engineer complex tissues, and build new models of human disease. However, reprogramming human somatic cells is an inefficient and nebulous, ill-defined process, and thus to benefit from the potential of iPS cell technology, it is essential to understand the mechanisms underlying cell fate transitions. Here, I explored the transcriptome dynamics of human cells as they acquire pluripotency and propose a novel model of modular-based reprogramming. My observations suggest that numerous common pathways observed during reprogramming are implemented in varying temporal orders across distinct systems, and show that disparate/opposing developmental programs can co-exist within individual cells. By applying a barcoded, single cell-tracing platform, I further identified a subpopulation of highly plastic cells that can access multiple cell fates, of which iPS cells is one of them. Moreover, I show that these cells elicit an elite gene signature that is shared with another highly plastic cell type shed from the kidneys that has elite reprogramming features. These results provide a new perspective on reprogramming as a non-linear process that requires a highly plastic intermediary cell state to achieve pluripotency. By applying this philosophy of reprogramming I propose that we can achieve a better understanding of cell fate control and propel more effective translation of stem cell biology.Ph.D