Human fibroblast reprogramming to pluripotent stem cells regulated by the miR19a/b-PTEN axis

Xiaoping He; Yang Cao; Lihua Wang; Yingli Han; Xiuying Zhong; Guixiang Zhou; Yongping Cai; Huafeng Zhang; Ping Gao

doi:10.1371/journal.pone.0095213

Human fibroblast reprogramming to pluripotent stem cells regulated by the miR19a/b-PTEN axis

PLoS One. 2014 Apr 16;9(4):e95213. doi: 10.1371/journal.pone.0095213. eCollection 2014.

Authors

Xiaoping He¹, Yang Cao¹, Lihua Wang¹, Yingli Han¹, Xiuying Zhong¹, Guixiang Zhou², Yongping Cai³, Huafeng Zhang¹, Ping Gao¹

Affiliations

¹ Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, China.
² Center for Reproductive Medicine, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China.
³ Department of Pathology, School of Medicine, Anhui University, Hefei, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation
Cell Line
Cellular Reprogramming*
Fibroblasts / cytology
Fibroblasts / metabolism*
Gene Expression Regulation
Genetic Vectors
Humans
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism*
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism
MicroRNAs / genetics
MicroRNAs / metabolism*
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism*
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA, Long Noncoding
Retroviridae / genetics
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism
Signal Transduction

Substances

KLF4 protein, human
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
MIR17HG, human
MIRN19 microRNA, human
MicroRNAs
Octamer Transcription Factor-3
POU5F1 protein, human
Proto-Oncogene Proteins c-myc
RNA, Long Noncoding
SOX2 protein, human
SOXB1 Transcription Factors
PTEN Phosphohydrolase
PTEN protein, human

Grants and funding

This work is supported in part by Chinese Academy of Sciences (XDA01010404), National Basic Key Research Program of China (2014CB910600, 2012CB910104 and 2011CBA01103), National Nature Science Foundation of China (31171385, 81372148 and 31071257). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.