Smad8/BMP2‐engineered mesenchymal stem cells induce accelerated recovery of the biomechanical properties of the achilles tendon

Abstract

Summary Tendon tissue regeneration is an important goal for orthopedic medicine. We hypothesized that implantation of Smad8/BMP2–engineered MSCs in a full-thickness defect of the Achilles tendon (AT) would induce regeneration of tissue with improved biomechanical properties. A 2 mm defect was created in the distal region of murine ATs. The injured tendons were then sutured together or given implants of genetically engineered MSCs (GE group), nonengineered MSCs (CH3 group), or fibrin gel containing no cells (FG group). Three weeks later the mice were killed, and their healing tendons were excised and processed for histological or biomechanical analysis. A biomechanical analysis showed that tendons that received implants of genetically engineered MSCs had the highest effective stiffness (> 70% greater than natural healing, p < 0.001) and elastic modulus. There were no significant differences in either ultimate load or maximum stress among the treatment groups. Histological analysis revealed a tendon-like structure with elongated cells mainly in the GE group. ATs that had been implanted with Smad8/BMP2–engineered stem cells displayed a better material distribution and functional recovery than control groups. While additional study is required to determine long-term effects of GE MSCs on tendon healing, we conclude that genetically engineered MSCs may be a promising therapeutic tool for accelerating short-term functional recovery in the treatment of tendon injuries.

Transcription factor EGR1 directs tendon differentiation and promotes tendon repair

“…This is consistent with the finding that the TGF-β ligand is a potent inducer of cartilage differentiation and is the main component of the chondrocyte differentiation medium in MSCs, although chondrocyte differentiation also requires cell adhesion (29,34). BMP is another signaling pathway involved in tendon cell differentiation (15,16,55), although the link between EGR1 and BMP remains to be established in the context of tendon lineage.…”

“…In addition, MSCs are not fully integrated into the host tissues, but appear to be important for their paracrine activity (19,23,56). This MSC property has led to the optimal therapy of combining MSCs with molecules that promote tendon repair (55,57,58). However, the question of which molecules to use still remains unanswered.…”

Tendon injury and repair – A perspective on the basic mechanisms of tendon disease and future clinical therapy

“…An important consequence of the involvement of the extrinsic compartment is the formation of a fibrotic scar [189,190]. Tendon scar tissue is generally characterized by resident cell phenotypes that differ from healthy tenocytes in morphology and function [139,191].…”

“…Thus, tendon healing after rupture involves complex coordination between the tendon proper and the vascular, nervous, and immune systems [18,[21][22][23]. Healing after such injuries generally results in a scar tissue that fails to re-establish tissue boundaries to appropriately compartmentalize the tissue [189,190]. This lack of compartmentalization may adversely affect tendon function (multi-scale structure-function) and may prevent a return to homeostasis of the tendon.…”

Biologics in Achilles tendon healing and repair: a review

“…When coexpressed with the intracellular protein Smad8, BMP-2 induces new tendon formation and blocks the differentiation of MSCs into cartilage and bone tissues. Achilles tendon defects in rats treated with Smad8/ BMP-2-engineered MSCs show accelerated early recovery of biomechanical properties as indicated by effective stiffness [57]. Furthermore, the use of BMP-2 in fibrin glue for the repair of a bone Achilles tendon injury in rats accelerates healing and improves the biomechanical and histological properties of the tissue [39].…”