Meniscus Injuries are among the most common conditions with a lack of effective treatment options^1,2. Stem cell-based regenerative treatments have emerged as a promising new alternative for meniscus repair³. However, the conflicting clinical outcomes of previous attempts at meniscus regeneration have significantly compromised its potential for practical application ^4-6.

The points we focused

This research discusses how we use pluripotent stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) in a clinic setting to treat patients with meniscus injury. IMRCs are a unique type of cells we developed that retain certain biological features of primary mesenchymal stem cells while possessing enhanced immune and matrix regulatory properties^7,8. The groundbreaking journey of our research, spanning from establishing the first clinical-grade stem cell bank in Beijing by the team at the Chinese Academy of Sciences in 2006, to conducting the first-in-human trial, is a testament to the potential of stem cell therapy in treating meniscus injuries. Our journey has been marked by overcoming numerous roadblocks, including sourcing seed cells for IMRC manufacturing (Fig. 1a), conducting systemic evaluations of cells during processing and in the final products, obtaining approval for clinical study use, and recruiting suitable volunteers.

What did we find?

Upon synovial fluid stimulation, IMRCs reacted much more promptly and efficiently compared to UCMSCs, with significantly increased expression of genes that are related to chondrocyte proliferation and vascular endothelial growth factor production (Fig. 1b). Additionally, they showed elevated expression of anti-inflammatory cytokine, immunomodulatory cytokines, and pro-regenerative cytokines. Their safety was validated in vivo in rabbits and cynomolgus monkeys and in vitro in the laboratory. Rabbits models that received IMRCs injection exhibit better meniscus regeneration than those received saline solution (Fig. 1c, d). The results of a phase I, dose-escalation clinical trial with eighteen participants in three groups showed that intra-articular injections of IMRCs are safe and effective with no adverse effects identified, particularly in the mid-dose (5 × 10⁷ cells) group (Fig. 1e).

Conclusion and future directions

Our preclinical experiment and clinical trial demonstrated the safety and efficacy of intra-articular injection of IMRCs for treating meniscus injury. The injured meniscus in the rabbit model showed significant repair, even though human IMRCs did not continuously remain at the site of meniscus focus, suggesting IMRCs-released cytokines are crucial for promoting meniscus repair. Additionally, our dosage-escalation first-in-human trial identified an optimal therapeutic dose, paving the way for future randomized, double-blind controlled clinical trials.

These heartwarming success stories serve as a beacon of hope and a testament to the potential of stem cell therapy in changing the lives of those suffering from meniscus injuries. Our journey, marked by trials and tribulations, has laid a solid foundation for the future, as we continue to delve into the untapped potential of stem cell therapy, with the ultimate goal of alleviating the pain and suffering of patients around the globe.

The impressed moments behind the clinical study

The first-in-human trial was a pivotal moment that showcased the transformative power of our novel stem cell therapy. One male participant, a devoted basketball player, had been rendered unable to indulge in his passion due to a sport-related meniscus injury. Post-stem cell transplantation, he was not only able to return to the basketball court but also regain his zest for life. Another remarkable story was that of a female participant from Henan Province, located 500 km away from our hospital. Initially wheelchair-bound, she experienced a miraculous transformation following an intra-articular injection of IMRCs, regaining the ability to stand and walk independently, free from the debilitating knee pain that had confined her to a wheelchair. At the trial's conclusion, she penned a beautiful poem as a token of gratitude, encouraging our team to continue their exploration into the unknown to benefit patients worldwide suffering from meniscus injuries.

This post is co-authored by Liangjiang Huang, Hong Chen, Jun Wu and Baoyang Hu.

Full text available at: https://www.nature.com/articles/s41392-023-01670-7.

References:

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2. Arnoczky, S.P. & Warren, R.F. Microvasculature of the human meniscus. Am J Sports Med 10, 90-95 (1982).
3. Rhim, H.C., et al. Mesenchymal stem cells for enhancing biological healing after meniscal injuries. World J Stem Cells 13, 1005-1029 (2021).
4. Vangsness, C.J., et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am 96, 90-98 (2014).
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8. Wu, J., et al. Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis. Cell Res 30, 794-809 (2020).