Cellular reprogramming for clinical cartilage repair

Britta J.H. Driessen, Colin Logie, Lucienne A. Vonk

The repair of articular cartilage needs a sufficient number of chondrocytes to replace the defect tissue, and therefore, expansion of cells is generally required. Chondrocytes derived by cellular reprogramming may provide a solution to the limitations of current (stem) cell-based therapies. In this article, two distinct approaches-induced pluripotent stem cell (iPSC)-mediated reprogramming and direct lineage conversion-are analysed and compared according to criteria that encompass the qualification of the method and the derived chondrocytes for the purpose of clinical application. Progress in iPSC generation has provided insights into the replacement of reprogramming factors by small molecules and chemical compounds. As follows, multistage chondrogenic differentiation methods have shown to improve the chondrocyte yield and quality. Nevertheless, the iPSC 'detour' remains a time- and cost-consuming approach. Direct conversion of fibroblasts into chondrocytes provides a slight advantage over these aspects compared to the iPSC detour. However, the requirement of constitutive transgene expression to inhibit hypertrophic differentiation limits this approach of being translated to the clinic. It can be concluded that the quality of the derived chondrocytes highly depends on the characteristics of the reprogramming method and that this is important to keep in mind during the experimental set-up. Further research into both reprogramming approaches for clinical cartilage repair has to include proper control groups and epigenetic profiling to optimize the techniques and eventually derive functionally stable articular chondrocytes.