The advances in regenerative medicine and cell-based therapies for cartilage regeneration have made these approaches get an edge over conventional surgical treatments. One of the most promising types of mesenchymal stem cells (MSCs) used in cartilage tissue engineering is the synovial fluid-derived mesenchymal stem cells (SF-MSCs). However, similar to other types of MSCs, self-renewal, differentiation, immunomodulation, and production of paracrine signals are not enough to cross the hurdles facing the clinical translation of SF-MSCs therapies for cartilage repair following injury or degeneration.
In an attempt to improve the employment of SF-MSCs in cartilage regeneration, induction of chondrogenic differentiation is key to success. Therefore, a research team from China tested a novel stem cell therapy for cartilage regeneration in osteoarthritis (OA) utilizing SF-MSCs and an exosome-based delivery system that controls the release of kartogenin (KGN), a recently discovered small molecule that promotes chondrogenic differentiation.
Despite its therapeutic potential, KGN has two major setbacks: first, it is hydrophobic and this complicates drug design; second, in high doses, it may induce hyperchondrogenesis. With the help of exosomes, a delivery system that controls the release of KGN can be achieved, but only after inducing selective activity towards SF-MSCs and improving their bioavailability. The latter can be attained by engineering the surface of exosomes, specifically by genetically modifying the surface protein lysosome-associated membrane glycoprotein 2b (Lamp2b) to harbor the MSC-binding peptide E7. The engineered SF-MSC/E7-Exo/KGN can then be delivered by an intra-articular (IA) injection. Below is a schematic illustration on engineering the desired exosome as presented in the original article.
Scheme 1. Schematic illustration on exosome engineering for enhanced delivery of KGN to SF-MSCs, and the co-injection of E7-Exo/KGN and SF-MSCs for cartilage regeneration and OA treatment.
After evaluating the therapeutic efficacy and safety of the SF-MSC/E7-Exo/KGN combination, authors concluded that this combination is superior to exosomes alone, MSC alone, or MSCs loaded with non-targeting exosome/KGN in reversing cartilage defects, and is a potentially safe treatment for OA. Although the obtained results highlight a novel strategy to deliver intact, small therapeutic molecules with unfavorable pharmacological properties, and to skip the use of synthetic polymers that exhibit low biocompatibility, a lot of questions remain unanswered and further research is needed.
For more information:
Xu, X., Liang, Y., Li, X., Ouyang, K., Wang, M., Cao, T., Li, W., Liu, J., Xiong, J., Li, B., Xia, J., Wang, D., & Duan, L. (2021). Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration. Biomaterials, 269, 120539. https://doi.org/10.1016/j.biomaterials.2020.120539