Emerging potential of gene silencing approaches targeting anti-chondrogenic factors for cell-based cartilage repair

Abstract

The field of cartilage repair has exponentially been growing over the past decade. Here, we discuss the possibility to achieve satisfactory regeneration of articular cartilage by means of human mesenchymal stem cells (hMSCs) depleted of anti-chondrogenic factors and implanted in the site of injury. Different types of molecules including transcription factors, transcriptional co-regulators, secreted proteins, and microRNAs have recently been identified as negative modulators of chondroprogenitor differentiation and chondrocyte function. We review the current knowledge about these molecules as potential targets for gene knockdown strategies using RNA interference (RNAi) tools that allow the specific suppression of gene function. The critical issues regarding the optimization of the gene silencing approach as well as the delivery strategies are discussed. We anticipate that further development of these techniques will lead to the generation of implantable hMSCs with enhanced potential to regenerate articular cartilage damaged by injury, disease, or aging.

Keywords: Anti-chondrogenic regulators; Cartilage repair; Chondrogenesis; Gene silencing; Mesenchymal stem cells; MicroRNA; RNA interference.

Fig. 1

Schematic representation of the production and transplantation of “silenced hMSCs” for improved cartilage repair. hMSCs can be collected from different sources including adult niches (e.g., bone marrow and adipose tissue) or perinatal tissues (e.g., placenta, amnios, and Wharton’s jelly of umbilical cord). Following transfection with RNAi molecules, “silenced hMSCs” with enhanced chondrogenic and therapeutic potential are generated. The cells are cultured in vitro for a certain amount of time to obtain an implantable construct, possibly by combination with a scaffold. Different parameters (cell number, oxygen concentration, use of a bioreactor) may be modified to optimize culture conditions and to mimic as much as possible the physiological microenvironment. Following implantation into the site of injury, neoformation of cartilage can be achieved, and tissue functionality can be restored as a result of diverse events potentially supported by the “silenced hMSCs”