Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells

Abstract

Cardiomyocyte regeneration is limited in adults. The adipose tissue-derived stromal vascular fraction (Ad-SVF) contains pluripotent stem cells that rarely transdifferentiate into spontaneously beating cardiomyocyte-like cells (beating CMs). However, the characteristics of beating CMs and the factors that regulate the differentiation of Ad-SVF toward the cardiac lineage are unknown. We developed a simple culture protocol under which the adult murine inguinal Ad-SVF reproducibly transdifferentiates into beating CMs without induction. The beating CMs showed the striated ventricular phenotype of cardiomyocytes and synchronised oscillation of the intracellular calcium concentration among cells on day 28 of Ad-SVF primary culture. We also identified beating CM-fated progenitors (CFPs) and performed single-cell transcriptome analysis of these CFPs. Among 491 transcription factors that were differentially expressed (≥ 1.75-fold) in CFPs and the beating CMs, myocyte-specific enhancer 2c (Mef2c) was key. Transduction of Ad-SVF cells with Mef2c using a lentiviral vector yielded CFPs and beating CMs with ~ tenfold higher cardiac troponin T expression, which was abolished by silencing of Mef2c. Thus, we identified the master gene required for transdifferentiation of Ad-SVF into beating CMs. These findings will facilitate the development of novel cardiac regeneration therapies based on gene-modified, cardiac lineage-directed Ad-SVF cells.

Integrative Bioinformatics Analysis Reveals That miR-524-5p/MEF2C Regulates Bone Metastasis in Prostate Cancer and Breast Cancer

“…In addition, MEF2C has close connections with uncontrolled cancer cell proliferation and enhanced invasion [ 45 ]. Regarding cancer metastasis, a recent study reported that MEF2C was consistently expressed in breast cancer brain metastases, and that its nuclear translocation was related to brain metastatic disease severity via VEGFR-2 and β -catenin signaling [ 46 ]. MEF2C was predicted to be regulated by miR-802-5p and miR-194-5p in brain metastases of breast cancer, which indicates that MEF2C plays a role in tumor metastasis.…”

Adipose tissue in bone regeneration - stem cell source and beyond

“…It has been reported that the SVF contains four different mesenchymal cells or progenitors or that the putative ADSCs are CD31-, CD34+/-, CD45-, CD90+, CD105-, CD117- and CD146-, the others being pericytes (CD146+/CD31-/CD34-), mature endothelial cells (CD31+/CD34-), progenitor endothelial cells (CD31+CD34+), and preadipocytes as CD31-/CD34+ cells[ 88 ]. ADSCs were reported to differentiate under controlled conditions in vitro to mesenchymal lineages (adipocytes, chondrocytes, osteoblasts and cardiomyocytes[ 89 ] and skeletal muscle[ 90 ]). Ectodermal (neurons, glia and Schwan cells) and endodermal (hepatocytes and pancreatic beta islet cells) ADSC conversion has been obtained[ 91 ].…”