The therapeutic effect of bone marrow-derived stem cell implantation after epiphyseal plate injury is abrogated by chondrogenic predifferentiation

The goal of this study was to determine the effects of chondrogenic predifferentiation on the ability of bone marrow-derived stromal cells (BMSCs) delivered to growth plate defects to restore growth function. Chondrogenesis was induced with transforming growth factor (TGF)-β1 treatment in high-density monolayer cultures of BMSCs in vitro. The predifferentiated or undifferentiated BMSCs were either seeded into agarose gels for continued in vitro culture, or injected into growth plate defects via an in situ gelling agarose. Predifferentiated BMSCs had higher Sox-9, type II collagen, and aggrecan mRNA levels compared to undifferentiated cells after high-density monolayer culture. After transfer to agarose gels, predifferentiated cells did not produce a cartilaginous matrix, even with continued TGF-β1 stimulation, whereas undifferentiated cells produced a cartilaginous matrix in this system. Three-dimensional images of the growth plate created from microcomputed tomography scans showed that delivery of either predifferentiated or undifferentiated cells to defects resulted in a decrease in mineralized tether formation (fusion) in the growth plate tissue surrounding the defect to normal levels. Limb length discrepancy between injured and control limbs was corrected after treatment with undifferentiated, but not predifferentiated, cells. These results indicate that cell therapy may be an effective treatment to reduce growth dysfunction after growth plate injury, perhaps by maintaining the health of the uninjured growth plate tissue, and that the cell differentiation state plays a role in restoring the growth potential of the injured limb.