Natural killer cells act as an extrinsic barrier for in vivo reprogramming

Abstract

The ectopic expression of transcription factors Oct4, Sox2, Klf4 and Myc (OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. However, little is known about the barriers that impair reprogramming in an in vivo context. We report that natural killer (NK) cells significantly limit reprogramming, both in vitro and in vivo. Cells and tissues at the intermediate states of reprogramming upregulate the expression of NK activating ligands, such as MULT1 and ICAM1. NK cells recognize and kill partially reprogrammed cells in a degranulation-dependent manner. Importantly, in vivo partial reprogramming is strongly reduced by adoptive transfer of NK cells, whereas it is significantly improved by depletion of NK cells. Notably, in the absence of NK cells, the pancreatic organoids derived from OSKM-expressing mice are remarkably large, suggesting the generation of cells with progenitor properties. We conclude that NK cells pose an important barrier for in vivo reprogramming, and this concept may apply to other contexts of transient cellular plasticity.