Is the in vitro chondrogenic potential of mesenchymal stem cells an indicator of their ability to repair cartilage tissue?

• Project/Area Number: 20K18053
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Okayama University (2021-2022); The University of Tokyo (2020)
• Principal Investigator: Chijimatsu Ryota 岡山大学, 大学病院, 助教 (60803210)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 軟骨再生 / 間葉系幹細胞 / 滑膜幹細胞 / 脂肪幹細胞 / 幹細胞治療 / 滑膜 / 軟骨 / 脂肪 / 再生医療 / 軟骨分化

Outline of Research at the Start

難治性組織である関節軟骨の損傷に対し、生体から単離培養した間葉系幹細胞(MSC)を軟骨欠損部へ移植する治療が国内外で試験されているものの、移植したMSCが直接軟骨へ分化することで組織修復を起こしているのかは意見が分かれている。一概にMSCと称しても、動物種や由来組織、培養法に起因する細胞性状の違いは大きいが、in vitroでの細胞の性質とin vivoでの軟骨修復能との関係は明らかでない。本研究では、各MSCが軟骨分化を起こすのに至適な条件を明らかにすると共に、軟骨治療に最適なMSCのin vitroでの選別法、調製法の開発を行う。

Outline of Final Research Achievements

We investigated the relationship between the chondrogenic differentiation ability of mesenchymal stem cells in vitro and their ability to repair cartilage in vivo following local transplantation for the treatment of articular cartilage defects. Analysis of in vitro data revealed that the differentiation factors necessary for chondrogenesis vary depending on the tissue origin and animal species of the stem cells. Among these factors, the responsiveness to TGFb in vitro yielded the most similar results to the response observed in vivo after transplantation. These findings suggest that the efficacy of stem cells for cartilage repair can be evaluated in vitro, and thus may be useful for developing strategies for cartilage treatment.

Academic Significance and Societal Importance of the Research Achievements

関節軟骨欠損への間葉系幹細胞の局所移植治療において、幹細胞の軟骨分化能と軟骨治療効果との関連性が期待される一方で、幹細胞を未分化な状態で移植しても分化しないとする報告が増えてきており、幹細胞の軟骨細胞への分化能の意義を見直す必要があった。
本研究により、生体内で分化する細胞種と分化しない細胞種をvitroで判別する手法が確立できており、今後の軟骨治療に有用な知見を提供できた。

Research Products

• [Journal Article] Cancer-specific tissue-resident memory T-cells express ZNF683 in colorectal cancer (2023)
  • Author(s): Kitakaze Masatoshi、Uemura Mamoru、Hara Tomoaki、Chijimatsu Ryota、Motooka Daisuke、Hirai Toshiro、Konno Masamitsu、Okuzaki Daisuke、Sekido Yuki、Hata Tsuyoshi、Ogino Takayuki、Takahashi Hidekazu、Miyoshi Norikatsu、Ofusa Ken、Mizushima Tsunekazu、Eguchi Hidetoshi、Doki Yuichiro、Ishii Hideshi
  • Journal Title: British Journal of Cancer Volume: - Issue: 10 Pages: 1828-1837
  • DOI: 10.1038/s41416-023-02202-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stem cell-based modeling and single-cell multiomics reveal gene-regulatory mechanisms underlying human skeletal development (2023)
  • Author(s): Tani Shoichiro, Okada Hiroyuki, Onodera Shoko, Chijimatsu Ryota, Seki Masahide, Suzuki Yutaka, Xin Xiaonan, Rowe David W., Saito Taku, Tanaka Sakae, Chung Ung-il, Ohba Shinsuke, Hojo Hironori
  • Journal Title: Cell Reports Volume: 42 Issue: 4 Pages: 112276-112276
  • DOI: 10.1016/j.celrep.2023.112276
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Runx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development (2022)
  • Author(s): Nagata K, Hojo H, Chang SH, Okada H, Chijimatsu R, Omata Y, Mori D, Makii Y, Kawata M, Kaneko T, Iwanaga Y, Nakamoto H, Maenohara Y, Tachibana N, Ishikura H, Higuchi J, Taniguchi Y, Ohba S, Chung Ul, Tanaka S, Saito T
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 6187-6204
  • DOI: 10.1038/s41467-022-33744-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RSPO2 defines a distinct undifferentiated progenitor in the tendon/ligament and suppresses ectopic ossification (2022)
  • Author(s): Tachibana N、Chijimatsu R、Okada H、Oichi T、Taniguchi Y、Maenohara Y、Miyahara J、Ishikura H、Iwanaga Y、Arino Y、Nagata K、Nakamoto H、Kato S、Doi T、Matsubayashi Y、Oshima Y、Terashima A、Omata Y、Yano F、Maeda S、Ikegawa S、Seki M、Suzuki Y、Tanaka S、Saito T
  • Journal Title: Science Advances Volume: 8 Issue: 33 Pages: 2138-2154
  • DOI: 10.1126/sciadv.abn2138
  • Peer Reviewed / Open Access
• [Journal Article] N(6)-methyladenosine methylation-regulated polo-like kinase 1 cell cycle homeostasis as a potential target of radiotherapy in pancreatic adenocarcinoma (2022)
  • Author(s): Tatekawa Shotaro、Tamari Keisuke、Chijimatsu Ryota、Konno Masamitsu、Motooka Daisuke、Mitsufuji Suguru、Akita Hirofumi、Kobayashi Shogo、Murakumo Yoshiki、Doki Yuichiro、Eguchi Hidetoshi、Ishii Hideshi、Ogawa Kazuhiko
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 11074-11074
  • DOI: 10.1038/s41598-022-15196-5
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a reference single-cell RNA sequencing dataset for human pancreatic adenocarcinoma (2022)
  • Author(s): Chijimatsu R、Kobayashi S、Takeda Y、Kitakaze M、Tatekawa S、Tachibana N、Saito T、Ennishi D、Tomida S、Sasaki K、Yamada D、Tomimaru Y、Takahashi H、Doki Y、Eguchi H
  • Journal Title: iScience Volume: 25 Issue: 8 Pages: 104659-104659
  • DOI: 10.1016/j.isci.2022.104659
  • Peer Reviewed / Open Access
• [Journal Article] Development of hydroxyapatite-coated nonwovens for efficient isolation of somatic stem cells from adipose tissues (2022)
  • Author(s): Chijimatsu Ryota、Takeda Taiga、Tsuji Shinsaku、Sasaki Kohei、Kato Koichi、Kojima Rie、Michihata Noriko、Tsubaki Toshiya、Matui Aya、Watanabe Miharu、Tanaka Sakae、Saito Taku
  • Journal Title: Regenerative Therapy Volume: 21 Pages: 52-61
  • DOI: 10.1016/j.reth.2022.05.009
  • Peer Reviewed
• [Journal Article] Techniques to detect epitranscriptomic marks (2022)
  • Author(s): Ofusa Ken、Chijimatsu Ryota、Ishii Hideshi
  • Journal Title: American Journal of Physiology-Cell Physiology Volume: - Issue: 4 Pages: C787-C793
  • DOI: 10.1152/ajpcell.00460.2021
  • Peer Reviewed / Open Access
• [Journal Article] Nematode-Applied Technology for Human Tumor Microenvironment Research and Development (2022)
  • Author(s): di Luccio Eric、Kaifuchi Satoru、Kondo Nobuaki、Chijimatsu Ryota、Vecchione Andrea、Hirotsu Takaaki、Ishii Hideshi
  • Journal Title: Current Issues in Molecular Biology Volume: 44 Issue: 2 Pages: 988-997
  • DOI: 10.3390/cimb44020065
• [Journal Article] Cancer metabolism challenges genomic instability and clonal evolution as therapeutic targets (2022)
  • Author(s): Takeda Yu、Chijimatsu Ryota、Ofusa Ken、Kobayashi Shogo、Doki Yuichiro、Eguchi Hidetoshi、Ishii Hideshi
  • Journal Title: Cancer Science Volume: 113 Issue: 4 Pages: 1097-1104
  • DOI: 10.1111/cas.15279
  • Peer Reviewed / Open Access
• [Journal Article] A novel nano-hydroxyapatite/synthetic polymer/bone morphogenetic protein-2 composite for efficient bone regeneration (2021)
  • Author(s): Bal Zeynep、Korkusuz Feza、Ishiguro Hiroyuki、Okada Rintaro、Kushioka Junichi、Chijimatsu Ryota、Kodama Joe、Tateiwa Daisuke、Ukon Yuichiro、Nakagawa Shinichi、Dede Eda iftci、Gizer Merve、Korkusuz Petek、Yoshikawa Hideki、Kaito Takashi
  • Journal Title: The Spine Journal Volume: 21 Issue: 5 Pages: 865-873
  • DOI: 10.1016/j.spinee.2021.01.019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TRPV2 is involved in induction of lubricin and suppression of ectopic endochondral ossification in articular joints (2021)
  • Author(s): Nakamoto Hideki、Katanosaka Yuki、Chijimatsu Ryota、Mori Daisuke、Xuan Fengjun、Yano Fumiko、Omata Yasunori、Maenohara Yuji、Murahashi Yasutaka、Kawaguchi Kohei、Yamagami Ryota、Inui Hiroshi、Taketomi Shuji、Taniguchi Yuki、Kanagawa Motoi、Naruse Keiji、Tanaka Sakae、Saito Taku
  • Journal Title: Arthritis & Rheumatology Volume: - Issue: 8 Pages: 1441-1450
  • DOI: 10.1002/art.41684
  • Peer Reviewed / Open Access
• [Journal Article] Divergence in chondrogenic potential between in vitro and in vivo of adipose- and synovial-stem cells from mouse and human (2021)
  • Author(s): Chijimatsu Ryota、Miwa Satoshi、Okamura Gensuke、Miyahara Junya、Tachibana Naohiro、Ishikura Hisatoshi、Higuchi Junya、Maenohara Yuji、Tsuji Shinsaku、Sameshima Shin、Takagi Kentaro、Nakazato Keiu、Kawaguchi Kohei、Yamagami Ryota、Inui Hiroshi、Taketomi Shuji、Tanaka Sakae、Saito Taku
  • Journal Title: Stem Cell Research & Therapy Volume: 12 Issue: 1
  • DOI: 10.1186/s13287-021-02485-5
  • Peer Reviewed / Open Access
• [Journal Article] Impact of One-Carbon Metabolism-Driving Epitranscriptome as a Therapeutic Target for Gastrointestinal Cancer (2021)
  • Author(s): Takeda Yu、Chijimatsu Ryota、Vecchione Andrea、Arai Takahiro、Kitagawa Toru、Ofusa Ken、Yabumoto Masami、Hirotsu Takaaki、Eguchi Hidetoshi、Doki Yuichiro、Ishii Hideshi
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 14 Pages: 7278-7278
  • DOI: 10.3390/ijms22147278
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Scent test using Caenorhabditis elegans to screen for early-stage pancreatic cancer (2021)
  • Author(s): Asai Ayumu、Konno Masamitsu、Ozaki Miyuki、Kawamoto Koichi、Chijimatsu Ryota、Kondo Nobuaki、Hirotsu Takaaki、Ishii Hideshi
  • Journal Title: Oncotarget Volume: 12 Issue: 17 Pages: 1687-1696
  • DOI: 10.18632/oncotarget.28035
  • Peer Reviewed / Open Access
• [Journal Article] Epithelial Cell Transformation and Senescence as Indicators of Genome Aging: Current Advances and Unanswered Questions (2021)
  • Author(s): Kitakaze Masatoshi、Chijimatsu Ryota、Vecchione Andrea、Kitagawa Toru、Doki Yuichiro、Eguchi Hidetoshi、Ishii Hideshi
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 14 Pages: 7544-7544
  • DOI: 10.3390/ijms22147544
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Amine modification of calcium phosphate by low-pressure plasma for bone regeneration (2021)
  • Author(s): Kodama Joe, et al
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-97460-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of osteoarthritis development by ADAM17/Tace in articular cartilage (2021)
  • Author(s): Kaneko Taizo、Horiuchi Keisuke、Chijimatsu Ryota、Mori Daisuke、Nagata Kosei、Omata Yasunori、Yano Fumiko、Inui Hiroshi、Moro Toru、Tanaka Sakae、Saito Taku
  • Journal Title: Journal of Bone and Mineral Metabolism Volume: 40 Issue: 2 Pages: 196-207
  • DOI: 10.1007/s00774-021-01278-3
  • Peer Reviewed
• [Journal Article] Concise review: Selecting the Source of Mesenchymal Stem Cells for Cartilage Regeneration Therapy (2021)
  • Author(s): Satoshi Miwa, Ryota Chijimatsu, Hideshi Ishii, Taku Saito
  • Journal Title: Journal of blood & lymph Volume: 11
  • Peer Reviewed / Open Access
• [Journal Article] Primary culture of mouse adipose and fibrous synovial fibroblasts under normoxic and hypoxic conditions (2020)
  • Author(s): SUGIMOTO Hikaru、MURAHASHI Yasutaka、CHIJIMATSU Ryota、MIWA Satoshi、YANO Fumiko、TANAKA Sakae、SAITO Taku
  • Journal Title: Biomedical Research Volume: 41 Issue: 1 Pages: 43-51
  • DOI: 10.2220/biomedres.41.43
  • NAID: 130007801491
  • ISSN: 0388-6107, 1880-313X
  • Year and Date: 2020-02-01
  • Peer Reviewed / Open Access
• [Journal Article] Enhancement of chondrogenic differentiation supplemented by a novel small compound for chondrocyte-based tissue engineering (2020)
  • Author(s): Hamamoto Shuichi、Chijimatsu Ryota、Shimomura Kazunori、Kobayashi Masato、Jacob George、Yano Fumiko、Saito Taku、Chung Ung-il、Tanaka Sakae、Nakamura Norimasa
  • Journal Title: Journal of Experimental Orthopaedics Volume: 7 Issue: 1 Pages: 446-458
  • DOI: 10.1186/s40634-020-00228-8
  • Peer Reviewed / Open Access
• [Journal Article] Associations of clinical outcomes and MRI findings in intra-articular administration of autologous adipose-derived stem cells for knee osteoarthritis (2020)
  • Author(s): Higuchi Junya、Yamagami Ryota、Matsumoto Takumi、Terao Tomohiro、Inoue Keita、Tsuji Shinsaku、Maenohara Yuji、Matsuzaki Tokio、Chijimatsu Ryota、Omata Yasunori、Yano Fumiko、Tanaka Sakae、Saito Taku
  • Journal Title: Regenerative Therapy Volume: 14 Pages: 332-340
  • DOI: 10.1016/j.reth.2020.04.003
  • Peer Reviewed / Open Access
• [Journal Article] Extracorporeal shock wave therapy accelerates endochondral ossification and fracture healing in a rat femur delayed-union model (2020)
  • Author(s): Kobayashi Masato、Chijimatsu Ryota、Yoshikawa Hideki、Yoshida Kiyoshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 530 Issue: 4 Pages: 632-637
  • DOI: 10.1016/j.bbrc.2020.07.084
  • Peer Reviewed
• [Journal Article] The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells (2020)
  • Author(s): Kushioka Junichi、Kaito Takashi、Chijimatsu Ryota、Okada Rintaro、Ishiguro Hiroyuki、Bal Zeynep、Kodama Joe、Yano Fumiko、Saito Taku、Chung Ung-il、Tanaka Sakae、Yoshikawa Hideki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 14190-14190
  • DOI: 10.1038/s41598-020-71193-6
  • Peer Reviewed / Open Access
• [Journal Article] A novel regulatory mechanism against BMP/Smad signaling by Smurf2 in bone (2020)
  • Author(s): Junichi Kushioka, Takashi Kaito, Rintaro Okada, Hiroyuki Ishiguro, Zeynep Bal, Joe Kodama, Ryota Chijimatsu, Melanie Pye, Masahiro Narimatsu, Jeffrey Wrana, Yasumichi Inoue, Hiroko Ninomiya, Shin Yamamoto, Takashi Saitou, Hideki Yoshikawa, Takeshi Imamura
  • Journal Title: Bone Research Volume: 8 Issue: 1 Pages: 41-41
  • DOI: 10.1038/s41413-020-00115-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evidence that TD‐198946 enhances the chondrogenic potential of human synovium‐derived stem cells through the NOTCH3 signaling pathway (2020)
  • Author(s): Kobayashi Masato、Chijimatsu Ryota、Hart David A.、Hamamoto Shuichi、Jacob George、Yano Fumiko、Saito Taku、Shimomura Kazunori、Ando Wataru、Chung Ung‐il、Tanaka Sakae、Yoshikawa Hideki、Nakamura Norimasa
  • Journal Title: Journal of Tissue Engineering and Regenerative Medicine Volume: 15 Issue: 2 Pages: 103-115
  • DOI: 10.1002/term.3149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lubricin Contributes to Homeostasis of Articular Cartilage by Modulating Differentiation of Superficial Zone Cells (2020)
  • Author(s): Maenohara Yuji、Chijimatsu Ryota、Tachibana Naohiro、Uehara Kosuke、Xuan Fengjun、Mori Daisuke、Murahashi Yasutaka、Nakamoto Hideki、Oichi Takeshi、Chang Song Ho、Matsumoto Takumi、Omata Yasunori、Yano Fumiko、Tanaka Sakae、Saito Taku
  • Journal Title: Journal of Bone and Mineral Research Volume: 36 Issue: 4 Pages: 792-802
  • DOI: 10.1002/jbmr.4226
  • Peer Reviewed / Open Access
• [Journal Article] Promoting Effect of Basic Fibroblast Growth Factor in Synovial Mesenchymal Stem Cell-Based Cartilage Regeneration (2020)
  • Author(s): Okamura G, Ebina K, Hirao M, Chijimatsu R, Yonetani Y, Etani Y, Miyama A, Takami K, Goshima A, Yoshikawa H, Ishimoto T, Nakano T, Hamada M, Kanamoto T, Nakata K.
  • Journal Title: Int J Mol Sci. Volume: 22 Issue: 1 Pages: 300-300
  • DOI: 10.3390/ijms22010300
  • Peer Reviewed / Open Access
• [Presentation] Rspo2/Prg4-Positive Cells Contribute to Ligament/Tendon Homeostasis Through Suppression of Ectopic Endochondral Ossification (2021)
  • Author(s): Naohiro Tachibana, Ryota Chijimatsu, Hiroyuki Okada, Yuki Taniguchi, Takeshi Oichi, Hideki Nakamoto, So Kato, Toru Doi, Yoshitaka Matsubayashi, Yasushi Oshima, Fumiko Yano, Shingo Maeda, Sakae Tanaka, Taku Saito
  • Organizer: ASBMR
  • Int'l Joint Research
• [Presentation] Motion is essential to maintain the synovial condition and joint homeostasis (2021)
  • Author(s): Hisatoshi Ishikura, Ryota Chijimatsu, Hiroyuki Okada, Yutaka Suzuki, Junya Miyahara, Yasunori Omata, Fumiko Yano, Sakae Tanaka, Taku Saito
  • Organizer: ASBMR
  • Int'l Joint Research
• [Presentation] Molecular mechanisms underlying adipose-derived stem cell therapy for osteoarthritis (2021)
  • Author(s): Junya Higuchi, Ryota Chijimatsu, Hisatoshi Ishikura, Fumiko Yano, Sakae Tanaka, Taku Saito
  • Organizer: ASBMR
  • Int'l Joint Research
• [Presentation] 関節運動は滑膜を介した関節恒常性維持機構に必須である (2021)
  • Author(s): 石倉 久年，千々松良太，岡田 寛之，鈴木 穣，宮原 潤也，矢野 文子，田中 栄，齊藤 琢
  • Organizer: 日本骨代謝学会
• [Presentation] scRNA-seqを用いた頚椎後縦靭帯骨化症の発症における疾患感受性遺伝子RSPO2の役割の検証 (2021)
  • Author(s): 立花 直寛，千々松良太，岡田 寛之，谷口 優樹，尾市 健，土肥 透，矢野 文子，前田 真吾，田中 栄，齋藤 琢
  • Organizer: 日本骨代謝学会
• [Presentation] 脂肪幹細胞による変形性関節症の病態制御機構 (2021)
  • Author(s): 樋口 淳也，千々松良太，石倉 久年，矢野 文子，田中 栄，齋藤 琢
  • Organizer: 日本骨代謝学会
• [Presentation] 抗コラーゲン抗体関節炎マウスを用いたbaricitinib の疼痛抑制作用の解析 (2021)
  • Author(s): 真壁 健太、小俣 康徳、淺香 明子、 柳原 大 、千々松 良太、 矢野 文子、田中 栄 、 齋藤 琢
  • Organizer: 日本整形外科学会