Mesenchymal stem cells from a hypoxic culture improve and engraft Achilles tendon repair

Tung-Fu Huang, Tu-Lai Yew, En-Rung Chiang, Hsiao-Li Ma, Chih-Yuan Hsu, Shan-Hui Hsu, Yuan-Tong Hsu, Shih-Chieh Hung
American Journal of Sports Medicine 2013, 41 (5): 1117-25

BACKGROUND: Bone marrow-derived mesenchymal stem cells (MSCs) from humans cultured under hypoxic conditions increase bone healing capacity.

HYPOTHESIS: Rat MSCs cultured under hypoxic conditions increase the tendon healing potential after transplantation into injured Achilles tendons.

STUDY DESIGN: Controlled laboratory study.

METHODS: Biomechanical testing, histological analysis, and bromodeoxyuridine (BrdU) labeling/collagen immunohistochemistry were performed to demonstrate that augmentation of an Achilles tendon rupture site with hypoxic MSCs increases healing capacity compared with normoxic MSCs and controls. Fifty Sprague-Dawley rats were used for the experiments, with 2 rats as the source of bone marrow MSCs. The cut Achilles tendons in the rats were equally divided into 3 groups: hypoxic MSC, normoxic MSC, and nontreated (vehicle control). The uncut tendons served as normal uncut controls. Outcome measures included mechanical testing in 24 rats, histological analysis, and BrdU labeling/collagen immunohistochemistry in another 24 rats.

RESULTS: The ultimate failure load in the hypoxic MSC group was significantly greater than that in the nontreated or normoxic MSC group at 2 weeks after incision (2.1 N/mm(2) vs 1.1 N/mm(2) or 1.9 N/mm(2), respectively) and at 4 weeks after incision (5.5 N/mm(2) vs 1.7 N/mm(2) or 2.7 N/mm(2), respectively). The ultimate failure load in the hypoxic MSC group at 4 weeks after incision (5.5 N/mm(2)) was close to but still significantly less than that of the uncut tendon (7.2 N/mm(2)). Histological analysis as determined by the semiquantitative Bonar histopathological grading scale revealed that the hypoxic MSC group underwent a significant improvement in Achilles tendon healing both at 2 and 4 weeks when compared with the nontreated or normoxic MSC group via statistical analysis. Immunohistochemistry further demonstrated that the hypoxic and normoxic MSC groups had stronger immunostaining for type I and type III collagen than did the nontreated group both at 2 and 4 weeks after incision. Moreover, BrdU labeling of MSCs before injection further determined the incorporation and retention of transplanted cells at the rupture site.

CONCLUSION: Transplantation of hypoxic MSCs may be a better and more readily available treatment than normoxic MSCs for Achilles tendon ruptures.

CLINICAL RELEVANCE: The present study provides evidence that transplantation of hypoxic MSCs may be a promising therapy for the treatment of Achilles tendon ruptures.

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