Human Fibroblast Reprogramming to Pluripotent Stem Cells Regulated by the miR19a/b-PTEN Axis

Induction of pluripotent stem cells (iPSC) by defined transcription factors is the recognized canonical means for somatic reprogramming, however, it remains incompletely understood how individual transcription factors affect cell fate decisions during the reprogramming process. Here, we report induction of fibroblast reprogramming by various transcriptional factors is mediated by a miR19a/b-PTEN axis. cMyc, one of the four Yamanaka factors known to stimulate both somatic cell reprogramming and tumorigenesis, induced the expression of multiple mircoRNAs, miR-17∼92 cluster in particular, in the early stage of reprogramming of human fibroblasts. Importantly, miR-17∼92 cluster could greatly enhance human fibroblast reprogramming induced by either the four Yamanaka factors (Oct4, Sox2, Klf4, and cMyc, or 4F) or the first three transcriptional factors (Oct4, Sox2, and Klf4, or 3F). Among members of this microRNA cluster, miR-19a/b exhibited the most potent effect on stimulating fibroblst reprogramming to iPSCs. Additional studies revealed that miR-19a/b enhanced iPSC induction efficiency by targeted inhibition of phosphatase and tensin homolog (PTEN), a renowned tumor suppressor whose loss-of-function mutations were found in multiple human malignancies. Our results thus demonstrate an important role of miR-19a/b-PTEN axis in the reprogramming of human fibroblasts, illustrating that the somatic reprogramming process and its underlying regulation pathways are intertwined with oncogenic signaling in human malignancies.