Abstract
Objective
Muscle‐derived stem cells (MDSCs) isolated from mouse skeletal muscle exhibit long‐time proliferation, high self‐renewal, and multipotent differentiation. This study was undertaken to investigate the ability of MDSCs that were retrovirally transduced to express bone morphogenetic protein 4 (BMP‐4) to differentiate into chondrocytes in vitro and in vivo and enhance articular cartilage repair.
Methods
Using monolayer and micromass pellet culture systems, we evaluated the in vitro chondrogenic differentiation of LacZ‐ and BMP‐4–transduced MDSCs with or without transforming growth factor β1 (TGFβ1) stimulation. We used a nude rat model of a full‐thickness articular cartilage defect to assess the duration of LacZ transgene expression and evaluate the ability of transplanted cells to acquire a chondrocytic phenotype. We evaluated cartilage repair macroscopically and histologically 4, 8, 12, and 24 weeks after surgery, and performed histologic grading of the repaired tissues.
Results
BMP‐4–expressing MDSCs acquired a chondrocytic phenotype in vitro more effectively than did MDSCs expressing only LacZ; the addition of TGFβ1 did not alter chondrogenic differentiation of the BMP‐4–transduced MDSCs. LacZ expression within the repaired tissue continued for up to 12 weeks. Four weeks after surgery, we detected donor cells that coexpressed β‐galactosidase and type II collagen. Histologic scoring of the defect sites 24 weeks after transplantation revealed significantly better cartilage repair in animals that received BMP‐4–transduced MDSCs than in those that received MDSCs expressing only LacZ.
Conclusion
Local delivery of BMP‐4 by genetically engineered MDSCs enhanced chondrogenesis and significantly improved articular cartilage repair in rats.