Abstract
Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx-expressing cells in sheath tissues, and its action is mediated through TGFβ/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair.
Highlights
Tendon injuries, commonly caused by overuse or age-related degeneration, are hard to repair and represent a major clinical challenge
Consistent with this work in mouse embryos, we found that Tubulin polymerization-promoting protein family member 3 (Tppp3) was expressed in adult tendon sheaths (Figure 1A)
Osteocalcin, which is encoded by the Bglap gene showed a specific expression pattern similar to that of Tppp3 in the sheath tissues
Summary
Commonly caused by overuse or age-related degeneration, are hard to repair and represent a major clinical challenge. It has been hypothesized that tendon heals through both intrinsic and extrinsic mechanisms in which cells from both within the tendons and the surrounding tissues are necessary for the healing process (Chang et al, 1997; de Mos et al, 2007; Gelberman et al, 1984; Harrison et al, 2003; Jones et al, 2003; Manske and Lesker, 1984; Peacock, 1965; Potenza, 1962; Salingcarnboriboon et al, 2003). Tendon fibers are enveloped by a dense membrane of connective tissues that are composed of epitenon and tendon sheaths, bridging blood vessels, lymphatics and nerves to tendon fibers (Elliott, 1965; Hess et al, 1989). Tendon sheaths are classified as extrinsic tissues in contrast to tendon fibers and epitenons, which are intrinsic structures (Kannus, 2000). Tendon sheath only covers tendon fibers in high friction areas where it provides lubrication for the functions of fibers comprising, for examples, the Tibialis anterior tendon, the peroneus longus and brevis tendon, and the
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