Reprogramming of human stem cells towards a rejuvenated and transformation-resisting state by recoding a single nucleotide

Premature senescence-associated functional decay and neoplastic transformation of transplanted human stem cells or their derivatives represent two major roadblocks for regenerative medicine. Cellular senescence acts as a major mechanism antagonizing neoplastic transformation, and stem cells evading senescence are prone to oncogenic transformation. So far it is unknown whether there is any genetic code, rewriting of which can simultaneously brake cellular senescence and oncogenic transformation programs. Here, we identify a single nucleotide in human genome(target on the transcription factor NRF2) as a candidate code, switch of which blocks both senescence and transformation pathways. Genetic modification stabilizes the wild type human mesenchymal stem cells (hMSCs) at a “sustainably younger” state. More importantly, the same genetic manipulation endows hMSCs with the ability of counteracting oncogenic transformation. Our study thus provides the first proof-of-concept of genetic enhancement of human stem cells, a strategy holding potential to generate superior and safer stem cell materials for cell replacement therapy. Overall design: RNA-seq of MSCs-NRF2 +/+_EP, MSCs-NRF2 AG/AG_EP, MSCs-NRF2 +/+_LP, MSCs-NRF2 AG/AG_LP, TMSCs-NRF2 +/+ and TMSCs-NRF2 AG/AG.

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Yang J, Li J, Suzuki K, Liu X, Wu J, Zhang W, Ren R, Zhang W, Chan P, Izpisua Belmonte JC, Qu J, Tang F, Liu GH