Transient transcription factor (OSKM) expression is key towards clinical translation of in vivo cell reprogramming

Abstract

Reprogramming adult, fully differentiated cells to pluripotency in vivo via Oct3/4, Sox2, Klf4 and c-Myc (OSKM) overexpression has proved feasible in various independent studies and could be used to induce tissue regeneration owing to the proliferative capacity and differentiation potential of the reprogrammed cells. However, a number of these reports have described the generation of teratomas caused by sustained reprogramming, which precludes the therapeutic translation of this technology. A recent study by the Izpisúa-Belmonte laboratory described a cyclic regime for short-term OSKM expression in vivo that prevents complete reprogramming to the pluripotent state as well as tumorigenesis. We comment here on this and other studies that provide evidence that in vivo OSKM induction can enhance tissue regeneration, while avoiding the feared formation of teratomas. These results could inspire more research to explore the potential of in vivo reprogramming in regenerative medicine.

Figure 1. The fine line between tumorigenesis and regeneration upon in vivo reprogramming

Various cell fate changes can be forced in vivo, albeit their outcomes differ. (a) Transdifferentiation drives direct conversion between specific cell types, but lacks the induction of cell division that maximizes the repopulation of an injured site; (b) sustained reprogramming to pluripotency leads to excessive and uncontrolled proliferation and random re‐differentiation into multiple lineages that results in the generation of teratomas; (c) in vivo reprogramming to a pluripotent or pluripotent‐like state may provide teratoma‐free tissue regeneration provided that the expression of pluripotency features and proliferation are strictly transient; (d) partial reprogramming is accompanied by transient proliferation that may replenish, among others, the pool of progenitor‐like cells crucial to maintain tissue homeostasis upon injury. This illustration has been adapted from the original idea of Waddington's epigenetic landscape.