Enthesis regeneration: a role for Gli1+ progenitor cells

Abstract

The tendon enthesis originates from a specific pool of hedgehogactive Gli1+ progenitor cells that differentiate and produce mineralized fibrocartilage. The current study investigated the regenerative capacity of this cell population by comparing the responses of early postnatal and mature entheses to injury. Lineage tracing studies demonstrated that the original Gli1+ cell population had the capacity to heal immature entheses after injury, but this capacity was lost after the cells differentiated into mature fibrochondrocytes. To further examine the involvement of Gli1+ cells and hedgehog signaling in enthesis healing, Gli1 expression was examined via lineage tracing approaches and the effect of Smo deletion was examined in the injured entheses. Immature injured entheses retained high levels of Gli1 expression, a marker of hedgehog activation, consistent with non-injured controls. In contrast, injured mature entheses had few Gli1+ cells early in the healing process, with limited recovery of the cell population later in the healing process. These results suggest that the presence of activated hedgehog signaling in enthesis cells early in the healing process may enhance healing of enthesis injuries by mimicking developmental processes.

Mkx-Deficient Mice Exhibit Hedgehog Signaling–Dependent Ectopic Ossification in the Achilles Tendons

“…Hedgehog signaling is crucial in endochondral ossification and involved in proper mineralization of the fibrocartilage cells within the enthesis, the tendon to bone insertion site . Gli1 is a transcription factor downstream of Hedgehog signaling .…”

“…Hedgehog signaling is crucial in endochondral ossification and involved in proper mineralization of the fibrocartilage cells within the enthesis, the tendon to bone insertion site. (40)(41)(42)(43)(44) Gli1 is a transcription factor downstream of Hedgehog signaling. (45,46) To investigate whether Hedgehog signaling activity is involved in Achilles tendon ossification in Mkx -/mice, we crossed mice carrying the Gli1 LacZ knock-in allele with Mkx -/mice and subsequently analyzed LacZ reporter activity in the Mkx -/mutant and control littermates.…”

Biologics and stem cell‐based therapies for rotator cuff repair

“…Although the majority of rodent rotator cuff studies have been carried out in rat, the mouse shoulder anatomy was recently shown to be comparable to rat and human. The very small size of the mouse rotator cuff precluded its use in earlier studies; however, novel microsurgical techniques have now been applied to successfully create partial and full detachment injuries with surgical repair, thereby opening new avenues for mechanistic research . Despite the numerous advantages of rat models, limitations include scar‐mediated healing (human tears do not undergo spontaneous healing), quadrupedal gait, and small scale relative to human .…”

“…The very small size of the mouse rotator cuff precluded its use in earlier studies; however, novel microsurgical techniques have now been applied to successfully create partial and full detachment injuries with surgical repair, thereby opening new avenues for mechanistic research. [18][19][20][21][22][23][24] Despite the numerous advantages of rat models, limitations include scar-mediated healing (human tears do not undergo spontaneous healing), quadrupedal gait, and small scale relative to human. 17 While joint replacement or other medical devices cannot be tested in rodent models, preclinical studies testing the efficacy of cell and biomolecule-based therapies are acceptable in rodents for meeting FDA standards.…”

Bone Surface Micro‐Topography at Craniofacial Entheses: Insights on Osteogenic Adaptation at Muscle Insertions

“…Collectively, these tissues define an enthesis and function to enact a force to the bone from muscle shortening while dissipating loads optimizing mechanical efficiency (Benjamin et al, 1986;Currey, 2002;Benjamin et al, 2004;Schwartz et al, 2013;Deymier et al, 2017). The micro structure (Sanchez et al, 2013;Beaulieu et al, 2016;Carbone et al, 2016;Cury et al, 2016;Zhao et al, 2017), mineral (Schwartz et al, 2012;Deymier et al, 2017), and protein composition (Cury et al, 2016), as well as the observed molecular signaling (Blitz et al, 2009;Carbone et al, 2016;Killian and Thomopoulos, 2016) and signatures of its cell populations (Zelzer et al, 2014;Schwartz et al, 2015;Schwartz et al, 2017) support the concept of enthesis as a discrete organ (Benjamin et al, 2004) with specific identifiable developmental processes, structure, composition, and function (Zelzer et al, 2014).…”