Tendon Extracellular Matrix: Tenogenic Activity on Mesenchymal Stem Cells and Utility in Tendon Tissue Engineering

Because of the limited and unsatisfactory outcomes of clinical tendon repair, tissue engineering approaches using adult mesenchymal stem cells (MSCs) are being considered a promising alternative healing strategy for injured tendon tissues. Successful and functional tendon tissue engineering depends on harnessing the biochemical cues presented by the native tendon extracellular matrix (ECM) and the embedded tissue-specific bio-factors. We have prepared and characterized the biological activities of a soluble extract of decellularized tendon ECM (tECM) on adult adipose derived stem cells (ASCs) on the basis of histological, biochemical, and gene expression analyses. Our results revealed the tenogenic effect of tECM on hASCs cultured in a 3-dimensional (3D) collagen scaffold under uniaxial tension. The presence of tECM also suppressed the osteogenic differentiation of hASCs induced by uniaxial tension and enhanced scaffold mechanical strength, accompanied by reduced expression and activity of matrix metalloproteinases (MMPs). Furthermore, we found that tECM enhanced the proliferation and TGF-β3 induced tenogenesis of ASCs, and modulated matrix deposition and organization by ASCs seeded in 3D fibrous scaffolds. These findings support the utility of tECM in creating bio-functional scaffolds for tendon tissue engineering. We also report here the development of a novel composite fibrous scaffold as a tendon graft fabricated by co-electrospinning of poly-e-caprolactone (PCL) and methacrylated gelatin (mGLT), which allowed the encapsulation of ASCs within the scaffold upon visible light induced gelatin photo-crosslinking, as well as the formation of stable, crosslinked multi-layered constructs. This scaffold design may improve cell-based tendon regeneration by serving as an effective reservoir of tECM and tenogenic growth factors to recapitulate the structural and biochemical characteristics of native tendon tissue. Our findings should lead to translational tissue engineering applications that will improve patient outcomes in the context of clinical tendon repair.