Led by Johnny Huard, PhD, director of the Growth and Development Laboratory at Children's Hospital of Pittsburgh and an associate professor in the departments of Orthopaedic Surgery and Molecular Genetics and Biochemistry and Bioengineering at the University of Pittsburgh School of Medicine, researchers induced damage to the knee joints in 36 12-week-old rats and divided them into three groups. Group 1 was treated with MDSCs embedded in fibrin glue. Group 2 was treated with MDSCs that had been cultured from 3-week-old rats and genetically engineered to express bone morphogenetic protein-4 (BMP-4). Group 3, the control group, was treated with fibrin glue.
The results showed well-integrated repaired tissue in the MDSC-B4 treatment group 8, 12 and 24 weeks after surgery, while the other two groups did not show as much improvement initially and by 24 weeks had deteriorated. "This finding indicates that continuous endogenous BMP-4 supplied by MDSCs genetically modified to express BMP-4 over an extended period of time can enhance articular cartilage healing," the authors state. They note that using fibrin glue enabled the cells to settle even in narrow clefts and has no adverse effects on cell viability.
The study also included culturing MDSC and MDSC-B4 in vitro in three different types of media and found that MDSC-B4 were able to differentiate into chondrogenic cells (cells that develop into cartilage) depending on the type of medium in which they grew. The addition of transforming grown factor â1 (TGFâ1) to MDSC-B4 did not enhance chondrogenic differentiation.
The authors conclude that skeletal muscle is a promising source of cells that can differentiate into cartilage-producing cells. "The MDSCs used here served as good carriers of a therapeutic gene and enabled the delivery of appropriate amounts of BMP-4 protein to the injury site," they state, adding that the improved repair lasted for 24 weeks following transplantation. Further studies conducted by the authors (not yet published) have produced similar results. They conclude: "These findings suggest that BMP-4 gene therapy based on retrovirally transduced MDSCs is a potential strategy by which to improve articular cartilage healing."
In an accompanying editorial in the same issue, Mary B. Goldring of the New England Baptist Bone and Joint Institute and Harvard Medical School in Boston, MA, notes that although stem cells derived from bone marrow have been extensively investigated for the repair of cartilage defects, the current study is the first to investigate using enriched stem cells from muscle. The author states that the results are encouraging, especially the successful use of fibrin glue to fill in the defect, and that the study "provides proof-of-principle for performing MDSC implantation in cartilage of adult humans, since 12-week-old rats are considered to be young adults." Although recent studies have suggested that fatty tissue and tissue lining the space between joints (synovium) might also be sources of stem cells, obtaining these cells is more invasive than muscle biopsies. The author also notes that patients could potentially serve as donors to themselves, since the current study used MDSCs from juvenile rats and other studies have shown such transplants to be problematic in adults. She concludes: "Thus, further work is warranted to determine the chondroprogenitor potential of MDSCs in adult humans and their capacity to form cartilage in vivo."
"Cartilage Repair Using Bone Morphogenetic Protein 4 and Muscle-Derived Stem Cells," Ryosuke Kuroda, Arvydas Usas, Seiji Kubo, Karin Corsi, Hairong Peng, Tim Rose, James Cummins, Freddie H. Fu, Johnny Huard, Arthritis & Rheumatism, February 2006; 54:2; pp. 433-442.
"Are Bone Morphogenetic Proteins Effective Inducers of Cartilage Repair? Ex Vivo Transduction of Muscle-Derived Stem Cells," Mary B. Goldring, Arthritis & Rheumatism, February 2006; 54:2; pp. 387-389.
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