Abstract
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.
Highlights
The past few years have seen a significant advance in reprogramming study following Shinya Yamanaka’s seminal discovery in 2006 [1]
While Induction of pluripotent stem cells (iPSC) generated by somatic reprogramming with transcription factors hold great promise in regenerative medicines for cell therapy, they pose many problems such as induction efficiency and safety concerns
We focused on the role of cMyc-mediated miRNAs in reprogramming of human fibroblasts
Summary
The past few years have seen a significant advance in reprogramming study following Shinya Yamanaka’s seminal discovery in 2006 [1]. Several studies have shown that mouse fibroblasts can be reprogrammed into iPSCs using nuclear factors that control lineage specification [7,8]. It seems that none of the initial four Yamanaka factors is essential for reprogramming induction [9]. Nowadays there is no doubt that pluripotency could be induced by various protocols pluripotency induction using defined transcription factors remains the recognized canonical means. It remains largely unclear how these transcription factors facilitate the reprogramming process
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