Harnessing endogenous stem/progenitor cells for tendon regeneration
Chang H. Lee, … , Guodong Yang, Jeremy J. Mao
Chang H. Lee, … , Guodong Yang, Jeremy J. Mao
Published June 8, 2015
Citation Information: J Clin Invest. 2015;125(7):2690-2701. https://doi.org/10.1172/JCI81589.
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Harnessing endogenous stem/progenitor cells for tendon regeneration

Abstract

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.

Authors

Chang H. Lee, Francis Y. Lee, Solaiman Tarafder, Kristy Kao, Yena Jun, Guodong Yang, Jeremy J. Mao

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Figure 6

Signaling study in CTGF-treated CD146+ tendon cells.

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Signaling study in CTGF-treated CD146+ tendon cells. Western Blot shows ...
Western Blot shows that CTGF treatment initiated FAK and ERK1/2 signaling (A). FAK and ERK1/2 were successfully KD using 100 nM Silencer siRNA with Neon system (Invitrogen) (B). FAK and ERK1/2 KD significantly attenuated the proliferation of CD146+ cells promoted by CTGF (C). FAK and ERK1/2 KD attenuated the elevated tendon-related gene expression by CTGF — including Col1a1, Col3a1, Tnc, Vim, and Scx — by 1 week. However, Tnmd expression was elevated with ERK1/2 KD (D). Control (Ctrl) indicates scrambled siRNA (n = 6 biological replicates per each group; *P < 0.01 compared with negative control). One-way ANOVA with post-hoc Tukey HSD was performed. All data are presented as mean ± SD.