There is an urgent need to create new and more effective therapies for tendon repair since injured tendons do not fully heal and regenerate. In acute tendon injuries, repair is carried out by intrinsic tendon cells and extrinsic cells that migrate from surrounding tissues and the circulation. The cells proliferate at the injured site, synthesize extracellular matrix, produce dense and aligned collagen fibers, and reorganize tendon structure to varying degrees. The repaired tendons can also undergo scarring and degeneration over time that are characterized by hypercellularity, mis-alignment and reduced number of collagen fibers, and increased production of cartilage-specific proteoglycans, among other defects. These alterations can result in loss of normal mechanical strength, flexibility and elasticity. It remains unclear as to which cells are responsible for the multistep repair process and which cellular actions should be enhanced or suppressed to prevent degenerative changes and improve healing. The elucidation of these and related issues could undoubtedly lead to development of new therapeutic tools to improve and stimulate tendon repair. We recently found that a cell population present at the injury site in mouse tendons exhibited progenitor-like traits including colony forming ability, multipotency and expression of mesenchymal stem cell surface markers. Interestingly, these injured tendon-associated progenitor cells, herein called inTPCs, possessed a much stronger ability to differentiate into chondrogenic cells than progenitor cells isolated from uninjured tendons. Furthermore, we found that agonists for the nuclear retinoic acid receptor ? (RAR?) stimulated tenogenic differentiation in cultured inTPCs, while they inhibited their chondrogenic differentiation in vitro and chondroid degeneration in ruptured mouse tendons in vivo. In addition, we found that mouse inTPCs participated in both repair process and degenerative changes in ruptured mouse tendons and that a similar cell population was present in injured human tendons. These and other results directly support and lead to our novel hypotheses that progenitor cells appearing in acutely injured tendons play important roles in tendon repair but also degeneration and that RAR? agonists can control their differential potential and improve tendon repair. This high risk-high return R21 project will test these novel possibilities using tendon progenitor cells in injured mouse and human tendons and will begin to develop methods to stimulate tendon repair by controlling differentiation of these progenitors toward a tenogenic lineage.
Our aims are: (1) To determine the effects of RAR? agonists on inTPCs and tendon repair in a mouse tendon injury model;and (2) To determine whether human inTPCs contribute to repair and degenerative changes in injured tendons and respond to RAR? agonists. The outcome of these exploratory experiments will pave the way toward designing more encompassing projects in which the above therapeutic strategies and their underlying mechanisms of action can be studied in greater depth, leading to innovative translational medicine outcomes in tendon repair.
Nearly 5 million patients visit a physician for tendon pain each year in the US and yet, current therapies for acute or chronic tendon damage and disorders remain ineffective. This project aims to study a new therapeutic target and a new drug treatment for tendon repair. The outcome of this study would have a strong socio-economical impact by reducing the burden of these conditions.
|Zhang, Kairui; Asai, Shuji; Hast, Michael W et al. (2016) Tendon mineralization is progressive and associated with deterioration of tendon biomechanical properties, and requires BMP-Smad signaling in the mouse Achilles tendon injury model. Matrix Biol 52-54:315-24|
|Zhang, Kairui; Asai, Shuji; Yu, Bin et al. (2015) IL-1Î² irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells inÂ vitro. Biochem Biophys Res Commun 463:667-72|
|Asai, Shuji; Otsuru, Satoru; Candela, Maria Elena et al. (2014) Tendon progenitor cells in injured tendons have strong chondrogenic potential: the CD105-negative subpopulation induces chondrogenic degeneration. Stem Cells 32:3266-77|