Myocardin‐related transcription factor‐A (MRTF‐A) is a key regulator of myofibroblast formation and function

Abstract

Myofibroblasts (MFs) are specialized contractile cells that arise from fibroblasts and facilitate wound closure and can promote pathological contractures. MFs have “super‐mature” focal adhesions and express α‐smooth muscle actin (ASMA) and other smooth muscle specific cytoskeletal proteins (SMCPs). Myocardin‐related transcription factor A (MRTF‐A/MAL/MKL‐1) is a putative mechanical stress‐induced co‐activator of serum response factor that activates expression of contractile proteins. We hypothesize that MRTF‐A is a key regulator of these contractile genes which allows for the formation and function of MFs. Rat embryonic fibroblasts (REF‐52) transfected with a constitutively active MRTF‐A acquired the MF phenotype as determined by increased expression of ASMA, SM22α, and smooth muscle γ‐actin (SMGA), as well as, an increased ability to contract a deformable silicone substrate. REF‐52 cells were treated with transforming growth factor‐β1 to promote MF formation. Small interfering RNA specific to MRTF‐A was used to knockdown expression of MRTF‐A in MFs, and resulted in decreased expression of ASMA, SM22α, and SMGA and decreased ability of MFs to contract a wrinkling substrate. These results suggest MRTF‐A functions as a regulator of MF formation by playing a critical role in regulating the expression of SMCPs and the resultant contractile activity. Funded by NIH grant R01 GM60651.