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Engraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect

Abe, Kengo Yamashita, Akihiro Morioka, Miho Horike, Nanao Takei, Yoshiaki Koyamatsu, Saeko Okita, Keisuke Matsuda, Shuichi Tsumaki, Noriyuki 京都大学 DOI:10.1038/s41467-023-36408-0

2023.02.20

概要

Induced pluripotent stem cells (iPSCs) are a promising resource for allogeneic cartilage transplantation to treat articular cartilage defects that do not heal spontaneously and often progress to debilitating conditions, such as osteoarthritis. However, to the best of our knowledge, allogeneic cartilage transplantation into primate models has never been assessed. Here, we show that allogeneic iPSC-derived cartilage organoids survive and integrate as well as are remodeled as articular cartilage in a primate model of chondral defects in the knee joints. Histological analysis revealed that allogeneic iPSC-derived cartilage organoids in chondral defects elicited no immune reaction and directly contributed to tissue repair for at least four months. iPSC-derived cartilage organoids integrated with the host native articular cartilage and prevented degeneration of the surrounding cartilage. Single-cell RNA-sequence analysis indicated that iPSC-derived cartilage organoids differentiated after transplantation, acquiring expression of PRG4 crucial for joint lubrication. Pathway analysis suggested the involvement of SIK3 inactivation. Our study outcomes suggest that allogeneic transplantation of iPSC-derived cartilage organoids may be clinically applicable for the treatment of patients with chondral defects of the articular cartilage; however further assessment of functional recovery long term after load bearing injuries is required.

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https://doi.org/10.1038/s41467-023-36408-0

Acknowledgements

Additional information

We thank Chieko Matsuda, Masumi Sanada, Hiroki Hagizawa, and Yuya

Nishijima for their assistance and helpful discussion. We thank the iPS

Cell Research Fund for its research support. This study was supported by

JSPS KAKENHI Grant No. 18H02923 (to N.T.) and WPI Premium Research

Institute for Human Metaverse Medicine (PRIMe) (to N.T.) from the Japan

Society for the Promotion of Science. This study was also supported by

the Center for Clinical Application Research on Specific Disease/

Organ (type B) Grant No. 21bm0304004h0009 (to N.T.); Research

Project for Practical Applications of Regenerative Medicine Grant No.

21bk0104079h0003 (to N.T.); Practical Research Project for Rare/

Intractable Diseases (step 1) Grant No. 21ek0109452h0002 (to N.T.);

Core Center for iPS Cell Research Grant No. 20bm0104001h0008 (to

N.T.); and the Acceleration Program for Intractable Diseases Research

utilizing disease-specific iPS cells Grant No. 20bm0804006h0004

(to N.T.) from the Japan Agency for Medical Research and Development (AMED).

Supplementary information The online version contains

supplementary material available at

https://doi.org/10.1038/s41467-023-36408-0.

Author contributions

K.A., S.M., and N.T. designed experiments. K.O. prepared cyiPSCs. A.Y.

created the cyiPS-cart. K.A. transplanted cyiPS-Carts into monkeys. K.A.

performed CT and histological analyses. K.A., M.M., S.K., and N.T. performed scRNA-seq analysis. N.H. and Y.T. performed experiments

regarding Sik3. K.A. and N.T. wrote the manuscript.

Competing interests

N.T. is an inventor and Kyoto University is a holder of the patent on

“An efficient chondrocyte induction method” (PCT/JP2014/079117).

This patent is licensed to Asahi KASEI corporation. Y.T. is an

employee of Asahi KASEI. The remaining authors declare no

competing interests.

Nature Communications | (2023)14:804

Correspondence and requests for materials should be addressed to

Noriyuki Tsumaki.

Peer review information Nature Communications thanks Denis

Evseenko and the other, anonymous, reviewer(s) for their contribution to

the peer review of this work. Peer reviewer reports are available.

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