In Vivo Cellular Reprogramming: The Next Generation

Abstract

Cellular reprogramming technology has created new opportunities in understanding human disease, drug discovery, and regenerative medicine. While a combinatorial code was initially found to reprogram somatic cells to pluripotency, a "second generation" of cellular reprogramming involves lineage-restricted transcription factors and microRNAs that directly reprogram one somatic cell to another. This technology was enabled by gene networks active during development, which induce global shifts in the epigenetic landscape driving cell fate decisions. A major utility of direct reprogramming is the potential of harnessing resident support cells within damaged organs to regenerate lost tissue by converting them into the desired cell type in situ. Here, we review the progress in direct cellular reprogramming, with a focus on the paradigm of in vivo reprogramming for regenerative medicine, while pointing to hurdles that must be overcome to translate this technology into future therapeutics.

Figure 1.

Conrad Waddington likened cell fate to a marble rolling downhill into one of several troughs representing fully differentiated cell types. Nuclear transfer and reprogramming showed that cells can be rolled back to the top of the hill by epigenetically altering the cell. Now, it is clear that cells can travel part way up the hill to roll back down a discrete number of troughs or even travel from one trough to another without going back up the hill at all, although the epigenetic barriers for such travel appear greater than traveling up hill.

Figure 2.

Schematic of approach to identify master regulatory factors capable of direct reprogramming in vitro and in vivo using cardiac reprogramming as example. A) Method for in vitro screening of developmentally critical transcription factors (TFs) that directly converted fibroblasts to an induced cardiomyocyte-like state. B) In vivo testing of reprogramming factors requires lineage tracing of cardiac fibroblasts as they transition into a new fate in the setting of injury. Introduction of cardiac reprogramming factors in vivo resulted in new conversion of resident fibroblasts into new cardiomyocyte-like that electrically integrated and contributed to improved cardiac function after injury.

Figure 3.

Schematic of sensory organ cells that could be harnessed for regenerative potential.