Muscle tissue engineering and regeneration through epigenetic reprogramming and scaffold manipulation

Sci Rep. 2015 Nov 9;5:16333. doi: 10.1038/srep16333.

Abstract

Efficiency of cell-based tissue engineering and regenerative medicine has been limited by inadequate cellular responses to injury because of aging and poor controllability of cellular interactions. Since cell progression is under a tight epigenetic regulation, epigenetic modulators such as 5-azacytidine (5-Aza-CR) have been utilized to facilitate reprogramming and development of somatic cells in 2-dimensional (2-D) settings. Nonetheless, progression of a specific tissue lineage toward the terminal phenotype is dependent not only on the genomic potential, but also on the microenvironment cues that are beyond the capability of 2-D approaches. In this study, we investigated the combined effects of matrices of variable rigidities and the treatment with the epigenetic modulator 5-Aza-CR on reprogramming adipose-derived stromal cells (ADSCs) into myoblast-like cells by utilizing tunable transglutaminase cross-linked gelatin (Col-Tgel) in vitro and in vivo. Our experiments demonstrated that cellular plasticity and trans-differentiation were significantly enhanced when ADSCs were treated with an effective dose of 5-Aza-CR (1.25 to 12.5 ng) in the optimal myogenic matrix (15 ± 5 kPa Col-Tgel). Our findings suggest that both physical signals and chemical milieu are critical for the regulation of cellular responses.

MeSH terms

  • Adipose Tissue / cytology
  • Animals
  • Azacitidine / pharmacology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cellular Reprogramming / genetics*
  • Epigenesis, Genetic*
  • Gene Silencing
  • Muscles*
  • Phenotype
  • Rats
  • Regeneration*
  • Regenerative Medicine*
  • Stromal Cells / cytology
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Tissue Engineering*
  • Tissue Scaffolds*
  • Transcriptional Activation

Substances

  • Azacitidine