Tendons have poor healing ability and require surgical repair with grafts when ruptured. The grafts are fraught with problems ranging from failure to donor site morbidity, motivating stem cell-based tissue engineering strategies for tissue replacement. However, differentiation of cells toward the tendon lineage (tenogenesis) has been challenging due in part to a poor understanding of tendon development. Developmental biology studies have demonstrated that muscle plays a significant role in tendon embryogenesis, though the mechanisms of its contributions are not well understood because the respective physical (mechanical) and soluble signaling factor influences of muscle tissue have been difficult to study in a complex in vivo environment. Our objective is to identify and characterize muscle cell-produced soluble and mechanical tenogenic cues to direct tenogenesis. We hypothesize that soluble factors secreted by muscle cells, as a function of their developmental stage, will regulate tenogenesis of TPCs in vitro and that this process will be enhanced by dynamic mechanical stimulation. Using a unique in vitro co-culture system we will characterize muscle cell secretion of putative soluble factors and their potential tenogenic roles (Aim 1), and investigate the potential for mechanical loading to enhance chemoregulation by studying TGF22 as a model soluble factor (Aim 2). The outcomes of this study will subsequently be translated in a future study to develop a mesenchymal stem cell-based regeneration strategy through controlled application of these influences. Our long-range goal is to use developmental biology as motivation and a guide in developing novel mesenchymal stem cell-based strategies in regenerating new tissue to replace injured or diseased tendons and ligaments. The outcome of this research effort would significantly advance knowledge of tendon developmental biology, help define rational soluble factor dosing and mechanical loading parameters for progenitor cell differentiation, and lead to advanced strategies to engineer tendons with mesenchymal stem cells.
This proposal is highly relevant to the improvement of public health as we envision that in the long-term, successful outcomes will enable innovative and efficient approaches to regenerating functional tendon. Thus, millions of patients that undergo surgical procedures for the repair or reconstruction of such tissues will ultimately benefit from this work.
|Marturano, Joseph E; Schiele, Nathan R; Schiller, Zachary A et al. (2016) Embryonically inspired scaffolds regulate tenogenically differentiating cells. J Biomech 49:3281-3288|
|Brown, Jeffrey P; Galassi, Thomas V; Stoppato, Matteo et al. (2015) Comparative analysis of mesenchymal stem cell and embryonic tendon progenitor cell response to embryonic tendon biochemical and mechanical factors. Stem Cell Res Ther 6:89|
|Brown, Jeffrey P; Finley, Violet G; Kuo, Catherine K (2014) Embryonic mechanical and soluble cues regulate tendon progenitor cell gene expression as a function of developmental stage and anatomical origin. J Biomech 47:214-22|
|Glass, Zachary A; Schiele, Nathan R; Kuo, Catherine K (2014) Informing tendon tissue engineering with embryonic development. J Biomech 47:1964-8|
|Schiele, Nathan R; Marturano, Joseph E; Kuo, Catherine K (2013) Mechanical factors in embryonic tendon development: potential cues for stem cell tenogenesis. Curr Opin Biotechnol 24:834-40|