Natural Killer Cells Oppose In Vivo Reprogramming

Research community is interested in the production of therapies to treat aging and age-related conditions based on partial reprogramming, exposing somatic cells to the Yamanaka factors for long enough to produce a rejuvenation of epigenetic patterns, but not long enough to change cell state. Reprogramming comes with an attendant risk of cancer, and reprogramming shares at least some molecular commonalities with the biochemistry of cancer cells, apparently enough so that the immune system will step in. The data presented in this paper supports a role for natural killer cells in destroying cells that are undergoing in vivo reprogramming. Evidently, this isn't enough to prevent benefits from occurring in past animal studies of reprogramming, but it may be a hurdle on the way to producing therapies for human patients.

The ectopic expression of the transcription factors OCT4, SOX2, KLF4, and MYC (Yamanaka factors, 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 in 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 increased by their depletion. Notably, in the absence of NK cells, the pancreatic organoids derived from OSKM-expressing mice are remarkably large, suggesting that ablating NK surveillance favours the acquisition of progenitor-like properties.

We conclude that NK cells pose an important barrier for in vivo reprogramming, and speculate that this concept may apply to other contexts of transient cellular plasticity.


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