Direct Reprogramming of Fibroblasts Into Smooth Muscle-Like Cells With Defined Transcription Factors—Brief Report

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Abstract

Objective—

To identify the transcription factors that could contribute to direct reprogramming of fibroblasts toward smooth muscle cell fate.

Approach and Results—

We screened various combinations of transcription factors, including Myocd (myocardin), Mef2C (myocyte enhancer factor 2C), Mef2B (myocyte enhancer factor 2B), Mkl1 (MKL [megakaryoblastic leukemia]/Myocd-like 1), Gata4 (GATA-binding protein 4), Gata5 (GATA-binding protein 5), Gata6 (GATA-binding protein 6), Ets1 (E26 avian leukemia oncogene 1, 5’ domain), and their corresponding carboxyterminal fusions to the transactivation domain of MyoD (myogenic differentiation 1)—indicated by *—for their effects on reprogramming mouse embryonic fibroblasts and human adult dermal fibroblasts to the smooth muscle cell fate as determined by the expression of specific markers. The combination of 3 transcription factors, Myocd (or Myocd*) with Mef2C (or Mef2C*) and Gata6, was the most efficient in enhancing the expression of smooth muscle marker genes and decreasing fibroblast gene expression. Additionally, the derived induced smooth muscle-like cells showed a contractile phenotype in response to carbachol.

Conclusions—

Combination of Myocd and Gata6 with Mef2C* (MG2*) could sufficiently and efficiently direct differentiation of mouse embryonic and human dermal fibroblasts into induced smooth muscle-like cells, thus opening new opportunities for disease modeling, tissue engineering, and personalized medicine.

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