Reduction of Fibrosis and Scar Formation by Partial Reprogramming In Vivo

Abstract

Transient expression of the transcription factors OCT4, SOX2, KLF4, and C-MYC (OSKM) to induce partial reprogramming while avoiding the pluripotent state and teratoma formation has recently been discussed as a strategy for regenerating damaged tissues in vivo, whereby the impact of partial reprogramming on tissue repair remains to be elucidated. Here, we activated OSKM transcription factors in cutaneous wounds of OSKM-inducible transgenic mice and found that induction of OSKM factors in excisional wounds caused a diminished fibroblast transdifferentiation to myofibroblasts and wound contraction. Gene expression analyses showed downregulation of the profibrotic marker genes transforming growth factor beta 1, Collagen I, and vascular endothelial growth factor. Consequently, histological analyses demonstrated that OSKM induction in incisional wounds resulted in reduced scar tissue formation. These data provide proof of concept that OSKM-mediated partial reprogramming in situ can diminish fibrosis and improve tissue healing with less scar formation without the risk of tumor formation. This new insight into the effects of partial reprogramming in vivo may be relevant for developing reprogramming-based regenerative therapies for tissue injury and fibrotic diseases. Stem Cells 2018;36:1216-1225.

Keywords: Cellular reprogramming; Fibrosis; In vivo Reprogramming; Regeneration; Wound healing.