Myocardin-related transcription factor-A is a key regulator in retinoic acid-induced neural-like differentiation of adult bone marrow-derived mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) have multilineage differentiation potential and can differentiate into neuron cells under appropriate environment in vitro and in vivo. Retinoic acid (RA), a vitamin A derivative, is known to facilitate the neuronal differentiation of MSCs. However, the mechanism by which RA induced MSC differentiation into neuron-like cells is not completely understood. Here, we show that RA can induce neural-like differentiation of bone marrow-derived MSCs, as evidenced by the increase of neuron-specific marker expression and the gradually decreased resting membrane potential. Of note, myocardin-related transcription factor-A (MRTF-A), a major co-activator of serum response factor (SRF), was significantly activated and its nuclear localization was observed during RA-induced neural-like differentiation. MRTF-A is recently reported to function in the development of the nervous system. Our results demonstrated that dominant-negative form of MRTF-A (DN-MRTF-A) or shRNA-MRTF-A strongly inhibited upregulation of neural markers in response to RA. Furthermore, reporter assays with NF-H promoter indicated that RA and MRTF-A can synergistically activate NF-H transcription and enhance the mRNA expression of NF-H. These findings reveal that MRTF-A is a key regulator in all-trans RA-induced neural-like differentiation of bone marrow-derived MSCs.