Effect of Muscle-Derived Stem Cells on Cartilage Repair
Articular cartilage possesses little ability for healing, leading to progressive destruction and eventually osteoarthritis in the setting of sustained injury. Current methods to repair damaged articular cartilage, including transplants of cartilage and bone, have had limited success due to a lack of durability and sustainability of the grafts. Here, Kuroda et al (Arthritis Rheum 2006; 54: 433) describe a set of in vitro and in vivo proof-of-concept experiments using muscle-derived stem cells (MDSCs) as chondroprogenitor cells genetically engineered to produce trophic factors essential for the growth and stability of newly formed articular cartilage.
Methods and Results:
In-vitro experiments: Mouse MDSCs were isolated and transfected with retroviral vectors expressing bone morphogenic protein-4 (BMP-4). Transfected and non-transfected MDSCs were monolayer plated or formed into cell pellets and co-cultured in either normal differentiation medium, fortified culture medium (CM), or CM supplemented with transforming growth factor b(TBFb).
Monolayer plated non-transfected MDSCs demonstrated Type II collagen producing colonies only when co-cultured in CM + TGFb. Transfected MDSCs produced significantly more Type II collagen producing colonies when cultured in CM, regardless of co-culture with TGFb.
Similarly, cell pellets of non-transfected MDSCs demonstrated extra-cellular matrix (ECM) production only when co-cultured in CM + TGFb. However, cell pellets of transfected MDSCs demonstrated dense ECM formation when co-cultured in either CM or CM + TGFb.
In-vivo experiments: Full-thickness articular cartilage defects were created in the knees of athymic rats. Cartilage defects were treated with transfected and non-transfected MDSCs embedded in fibrin glue. Chondrocyte differentiation and histologic evaluation of cartilage repair was performed at 4, 8, 12, and 24 weeks after implantation.
Transplants of transfected MDSCs demonstrated chodrocyte differentiation with robust and durable production of ECM with a histologic appearance indistinguishable from normal hyaline cartilage up to 24 weeks after implantation. In contrast, non-transfected MDSCs demonstrated little to no chodrocyte differentiation, progressive thinning, and a lack of bonding to adjacent undamaged articular cartilage.
Conclusion: Cartilage repair in rats was enhanced by the transplantation of MDSCs genetically engineered to express BMP-4.
Editorial Comment: These are a very exciting series of proof-of-concept experiments demonstrating a novel method of cartilage repair, one which holds promise for application in human disease. The use of locally delivered intra-articular gene therapy for osteoarthritis is particularly compelling, since osteochondral transplants and systemic therapies have thus far demonstrated limited efficacy.
Questions that remain to be answered prior to human application include whether the stem cell transplants will be self-sustaining or whether repeat transplants would be required. In addition, the effect of sustained delivery of trophic factors on undamaged native cartilage will require investigation, as the development of osteochondral hyperplasia and even malignancy is possible with the use of this method.