Discussion
TGF-β1, meniscus injury, avascular
The meniscus has limited healing capacity, especially the avascular zone that occupies two-thirds of the meniscus. We have shown that intra-articular injection of hESCs-derived IMRCs enables the endogenous regeneration of injured meniscus in rabbits. This is likely achieved by modulating the injured environment as the IMRCs possess strong immunomodulatory and pro-regenerative gene profiles in response to the synovial fluids from patients with meniscus injury. Our phase I clinical trial showed that intra-articular injection of IMRCs is not only safe but also beneficial based on improvement in symptoms and MRI imaging. Our dose-escalation study further identified an optimal dose for treatment, setting the foundation for further clinical studies.Many pre-clinical studies suggested MSC-based regenerative treatment is a promising option to overcome poor intrinsic healing capacity, including synovial-derived MSCs (S-MSCs),The substantial pro-regenerative capacity of the IMRCs prompted us to examine their properties and compare them with other types of MSCs, especially UCMSCs. In previous vitro studies, the levels of IL-6, MCP-1, PEG2, and TGF-β1 in UCMSCs supernatants were increased, and UCMSCs were able to significantly reduce the production of IL-6 and IL-12 when activated by M1 macrophages.With the safety profiles in rabbits and monkeys, we conducted the phase I clinical trial. Our results show that intra-articular injection of IMRCs is safe, similar to previous reports using various types of MSCs,Importantly, we identified an ideal dose (5 × 10Taken together, despite the small sample size and absence of the control group, this study provides robust evidence that IMRCs are safe for meniscus injury and can promote meniscus regeneration and healing, as well as sufficient proof-of-concept (POC) data to justify further randomized, double-blind controlled clinical trials.