MicroRNA-mediated regulation of extracellular matrix formation modulates somatic cell reprogramming

Abstract

Somatic cells can be reprogrammed to reach an embryonic stem cell-like state by overexpression of defined factors. Recent studies have greatly improved the efficiency of the reprogramming process but the underlying mechanisms regulating the transition from a somatic to a pluripotent state are still relatively unknown. MicroRNAs (miRs) are small noncoding RNAs that primarily regulate target gene expression post-transcriptionally. Here we present a systematic and comprehensive study of microRNAs in mouse embryonic fibroblasts (MEFs) during the early stage of cell fate decisions and reprogramming to a pluripotent state, in which significant transcriptional and epigenetic changes occur. One microRNA found to be highly induced during this stage of reprogramming, miR-135b, targeted the expression of extracellular matrix (ECM) genes including Wisp1 and Igfbp5. Wisp1 was shown to be a key regulator of additional ECM genes that serve as barriers to reprogramming. Regulation of Wisp 1 is likely mediated through biglycan, a glycoprotein highly expressed in MEFs that is silenced in reprogrammed cells. Collectively, this report reveals a novel link between microRNA-mediated regulation of ECM formation and somatic cell reprogramming, and demonstrates that microRNAs are powerful tools to dissect the intracellular and extracellular molecular mechanisms of reprogramming.