Stem cell-based therapies have been touted as a promising tool for tissue regeneration. While this approach has seen some success, current stem cell-based regenerative treatments involve isolating the desired population and manipulating these cells ex vivo to encourage expansion and generation of the desired progenitor cell prior to transplantation. Most tissues harbor a small population of endogenous stem cells with regenerative capacity, and recent evidence indicates that targeted expansion and activation of these cells can promote tissue repair. Chang Lee and colleagues at Columbia University Medical Center demonstrate that tendon-resident stem/progenitor cells (TSCs) can be harnessed for regeneration of injured tendons in rats. The authors identified a population of CD146+ multipotent, clonogenic cells that were present in tendons and could be enriched by treatment with connective tissue growth factor (CTGF), which activated ERK1/2 and focal adhesion kinase. In a patellar tendon transection model, animals treated with CTGF and fibrin gel exhibited enhanced tendon healing compared with animals that had received fibrin gel alone. Moreover, healing tendons of CTGF-treated animals had increased numbers of CD146+ cells and greater collagen deposition at the site of injury, and the collagen fiber organization in treated tendons was similar to that of uninjured tendons. The results of this study demonstrate that endogenous stem cell populations can be enhanced to promote tissue regeneration. The accompanying image shows collagen fiber orientation within native tendon (right), untreated injured tendon (center), and injured CTGF-treated tendon. Note the collagen fibers in the CTGF-regenerated tendon and native tendon are similarly organized, whereas the collagen fibers in the untreated injured tendon are unorganized and scar like.
Current stem cell–based strategies for tissue regeneration involve ex vivo manipulation of these cells to confer features of the desired progenitor population. Recently, the concept that endogenous stem/progenitor cells could be used for regenerating tissues has emerged as a promising approach that potentially overcomes the obstacles related to cell transplantation. Here we applied this strategy for the regeneration of injured tendons in a rat model. First, we identified a rare fraction of tendon cells that was positive for the known tendon stem cell marker CD146 and exhibited clonogenic capacity, as well as multilineage differentiation ability. These tendon-resident CD146+ stem/progenitor cells were selectively enriched by connective tissue growth factor delivery (CTGF delivery) in the early phase of tendon healing, followed by tenogenic differentiation in the later phase. The time-controlled proliferation and differentiation of CD146+ stem/progenitor cells by CTGF delivery successfully led to tendon regeneration with densely aligned collagen fibers, normal level of cellularity, and functional restoration. Using siRNA knockdown to evaluate factors involved in tendon generation, we demonstrated that the FAK/ERK1/2 signaling pathway regulates CTGF-induced proliferation and differentiation of CD146+ stem/progenitor cells. Together, our findings support the use of endogenous stem/progenitor cells as a strategy for tendon regeneration without cell transplantation and suggest this approach warrants exploration in other tissues.
Chang H. Lee, Francis Y. Lee, Solaiman Tarafder, Kristy Kao, Yena Jun, Guodong Yang, Jeremy J. Mao