Mohawk Promotes the Tenogenesis of Mesenchymal Stem Cells Through Activation of the TGFβ Signaling Pathway

Stem Cells. 2015 Feb;33(2):443-55. doi: 10.1002/stem.1866.

Abstract

The transcription factor Mohawk (Mkx) is expressed in developing tendons and is an important regulator of tenogenic differentiation. However, the exact roles of Mkx in tendinopathy and tendon repair remain unclear. Using gene expression Omnibus datasets and immunofluorescence assays, we found that Mkx expression level was dramatically lower in human tendinopathy tissue and it is activated at specific stages of tendon development. In mesenchymal stem cells (MSCs), ectopic Mkx expression strikingly promoted tenogenesis more efficiently than Scleraxis (Scx), a well-known master transcription factor of tendon. Significantly higher levels of tenogenic gene expression and collagen fibril growth were observed with Mkx versus Scx. Interestingly, it was observed that Mkx dramatically upregulated Scx through binding to the Tgfb2 promoter. Additionally, the transplantation of Mkx-expressing-MSC sheets promoted tendon repair in a mouse model of Achilles-tendon defect. Taken together, these data shed light on previously unrecognized roles of Mkx in tendinopathy, tenogenesis, and tendon repair as well as in regulating the TGFβ pathway.

Keywords: Differentiation; Mesenchymal stem cells; Mohawk; TGF-ß; Tendon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Line
  • Databases, Genetic
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Mesenchymal Stem Cells / metabolism*
  • Mesenchymal Stem Cells / pathology
  • Mice
  • Mice, Transgenic
  • Organogenesis*
  • Signal Transduction*
  • Tendinopathy / genetics
  • Tendinopathy / metabolism
  • Tendinopathy / pathology
  • Tendons / metabolism*
  • Tendons / pathology
  • Transforming Growth Factor beta2 / genetics
  • Transforming Growth Factor beta2 / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • SCXA protein, human
  • Scx protein, mouse
  • TGFB2 protein, human
  • Tgfb2 protein, mouse
  • Transforming Growth Factor beta2
  • mohawk protein, human
  • mohawk protein, mouse