D. Evseenko (Los Angeles, US)Keck School of Medicine of USC Orthopaedic Surgery, Stem Cell Research
Presenter Of 2 Presentations
12.1.6 - Long-Term Repair of Porcine Articular Cartilage Using Clinically Compatible Human Stem Cell-Derived Chondrocytes
The pathogenesis of osteoarthritis often begins from an injury such as a focal defect to articular cartilage, which establishes chronic, low-grade inflammation that eventually results in degenerative joint disease. Pluripotent stem cell-derived articular chondrocytes represent a promising new tool for articular cartilage repair.
Methods and Materials
Research-grade human pluripotent stem cells (hPSC) were differentiated into immature articular chondrocytes using protocols previously established in our lab. Generated hPSC-derived chondrocytes (hPSDC) were seeded onto clinical grade collagen 1/3 membranes (hPSDC-M) and evaluated using single-cell RNA-sequencing to characterize and assess the developmental status. Potential of engraftment of the hPSDC-M was assessed in a porcine model, where 6-mm full thickness defects were generated in the articular cartilage of male Yucatan minipigs.
Our studies have shown that transcriptional signatures of hPSDC-M via single cell sequencing closely resemble embryonic and juvenile stages of human chondrocyte ontogeny, suggesting an immature chondrogenic identity. Our porcine model also demonstrated that implanted hPSDC-M engrafted and contributed to the generation of comparable articular cartilage tissue endogenously found when compared to the membranes alone. Engrafted human chondrocytes were clearly detectable at 6 months after implantation in all tested animals. Biomechanical assessment after 6 months confirmed that the cartilage containing the hPSDC-M showed significant improvement in cartilage surface biomechanical properties compared to the membrane alone. which, and positively stained for GAGs, PRG4, collagen 2, and SOX9 via IHC. Human hPSDC-M secreted nearly 10-fold more BMP2 than BMSCs indicating that pluripotent stem cells closely resemble chondroinductive signature of early perichondrium, while adult MSCs lacked this potential.
Both the functionality by engraftment of these immature chondrocytes and their paracrine activity contribute to the value of hPSDC-M, which has the potential to enact articular cartilage repair as a universal, off-the-shelf product from an inexhaustible source of chondrogenic cells.
16.1.9 - Novel Small Molecule Modulator of the gp130 Receptor shows Dose-Dependent Therapeutic Efficacy in a Canine Model of Osteoarthritis
The pathogenesis of osteoarthritis (OA) often begins from an injury to articular cartilage, which establishes chronic, low-grade inflammation principally mediated by IL-6 family cytokines that signal through the obligate receptor gp130. However, we and others have shown that gp130 can also regulate anabolic responses in chondrocytes and immune system. Here, we unveil an advanced late pre-clinical regeneration-promoting candidate CX-011 that modulates, rather than completely inhibits, gp130 signaling.
Methods and Materials
Twenty-four purpose bred Foxhound dogs (12 females, 12 males), 10 months of age, (Marshall BioResources) were chosen for this study. All dogs underwent CT imaging of both knee joints then general anesthesia and arthroscopic surgery to induce OA by medial meniscal release (MMR). Three groups received CX-011 by intra-articular injection into the operated limb and the fourth control group (n=6) received an equal volume of vehicle. Injections were done four weeks post-operatively and again at 6 weeks after initial injection. The three experimental groups given the test article received doses of 10 μg, 1 μg or 0.1 μg in a 0.5 mL volume.
Dose dependent effects of CX-11 were documented. In the highest dose of CX-011 (10 mg) group, there was highly significant chondroprotection (p = 0.012). Synovial inflammation was significantly limited by the two highest dose rates (p = 0.016) of the test article. CT imaging showed a dramatic, statistically significant reduction (p < 0.001) in shape alteration in dogs treated with the two highest dose levels of CX-011 compared to controls. Finally, the two highest doses had significantly reduced lameness, indicating lower pain levels with increasing test article concentration (p < 0.001).
The current study has nominated the gp130 modulator CX-011 as an excellent candidate for clinical progression as a disease modifying agent for OA with concurrent reduction in pain.
Meeting Participant Of
Basic Science Committee Meeting
- M. Wimmer (Chicago, US)
- S. Nürnberger (Vienna, AT)
- C. Pascual Garrido (St. Louis, US)
- D. Haudenschild (Sacramento, US)
- J. Guicheux (Nantes, FR)
- L. Goodrich (Fort Collins, US)
- D. Evseenko (Los Angeles, US)
- A. Mobasheri (Vilnius, LT)
- L. Vonk (Teltow, DE)
- L. Gao (Homburg, DE)
- M. Sato (Isehara, JP)
- B. Grigolo (Bologna, IT)
- M. Stoddart (Davos Platz, CH)