Evidence that TD-198946 enhances the chondrogenic potential of human synovium-derived stem cells through the NOTCH3 signaling pathway
Masato Kobayashi
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorRyota Chijimatsu
Bone and Cartilage Regenerative Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorDavid A. Hart
McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Canada
Search for more papers by this authorShuichi Hamamoto
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorGeorge Jacob
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorFumiko Yano
Bone and Cartilage Regenerative Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorTaku Saito
Sensory and Motor System Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorKazunori Shimomura
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorWataru Ando
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorUng-il Chung
Center for Disease Biology and Integrative Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorSakae Tanaka
Sensory and Motor System Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorHideki Yoshikawa
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorCorresponding Author
Norimasa Nakamura
Institute for Medical Science in Sports, Osaka Health Science University, Osaka, Japan
Correspondence:
Norimasa Nakamura, Osaka Health Science University Graduate School Sports Medical Science Laboratory, 1-9-27, Tennma, Kita-ku, Osaka, Japan.
Email: [email protected]
Search for more papers by this authorMasato Kobayashi
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorRyota Chijimatsu
Bone and Cartilage Regenerative Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorDavid A. Hart
McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Canada
Search for more papers by this authorShuichi Hamamoto
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorGeorge Jacob
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorFumiko Yano
Bone and Cartilage Regenerative Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorTaku Saito
Sensory and Motor System Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorKazunori Shimomura
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorWataru Ando
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorUng-il Chung
Center for Disease Biology and Integrative Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorSakae Tanaka
Sensory and Motor System Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Search for more papers by this authorHideki Yoshikawa
Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Search for more papers by this authorCorresponding Author
Norimasa Nakamura
Institute for Medical Science in Sports, Osaka Health Science University, Osaka, Japan
Correspondence:
Norimasa Nakamura, Osaka Health Science University Graduate School Sports Medical Science Laboratory, 1-9-27, Tennma, Kita-ku, Osaka, Japan.
Email: [email protected]
Search for more papers by this authorAbstract
Human synovium-derived stem cells (hSSCs) are an attractive source of cells for cartilage repair. At present, the quality of tissue and techniques used for cartilage regeneration have scope for improvement. A small compound, TD-198946, was reported to enhance chondrogenic induction from hSSCs; however, other applications of TD-198946, such as priming the cell potential of hSSCs, remain unknown. Our study aimed to examine the effect of TD-198946 pretreatment on hSSCs. HSSCs were cultured with or without TD-198946 for 7 days during expansion culture and then converted into a three-dimensional pellet culture supplemented with bone morphogenetic protein-2 (BMP2) and/or transforming growth factor beta-3 (TGFβ3). Chondrogenesis in cultures was assessed based on the GAG content, histology, and expression levels of chondrogenic marker genes. Cell pellets derived from TD-198946-pretreated hSSCs showed enhanced chondrogenic potential when chondrogenesis was induced by both BMP2 and TGFβ3. Moreover, cartilaginous tissue was efficiently generated from TD-198946-pretreated hSSCs using a combination of BMP2 and TGFβ3. Microarray analysis revealed that NOTCH pathway-related genes and their target genes were significantly upregulated in TD-198946-treated hSSCs, although TD-198946 alone did not upregulate chondrogenesis related markers. The administration of the NOTCH signal inhibitor diminished the effect of TD-198946. Thus, TD-198946 enhances the chondrogenic potential of hSSCs via the NOTCH3 signaling pathway. This study is the first to demonstrate the gradual activation of NOTCH3 signaling during chondrogenesis in hSSCs. The priming of NOTCH3 using TD-198946 provides a novel insight regarding the regulation of the differentiation of hSSCs into chondrocytes.
CONFLICT OF INTEREST
All authors have no conflict of interest to declare.
AUTHOR CONTRIBUTIONS
Masato Kobayashi and Ryota Chijimatsu took responsibility for the integrity of the work as a whole, from inception to the completed manuscript. Conception and design: Masato Kobayashi, Ryota Chijimatsu, Hideki Yoshikawa, and Norimasa Nakamura. Analysis and interpretation of the data, statistical expertise: Masato Kobayashi, Ryota Chijimatsu, David A. Hart, Shuichi Hamamoto, Fumiko Yano, Taku Saito, Kazunori Shimomura, Wataru Ando, Ung-il Chung, Sakae Tanaka, Hideki Yoshikawa, and Norimasa Nakamura. Administrative, technical, or logistic support: Masato Kobayashi and Ryota Chijimatsu, David A. Hart, Shuichi Hamamoto, Fumiko Yano, Taku Saito, Kazunori Shimomura, Wataru Ando, Ung-il Chung, Sakae Tanaka, Hideki Yoshikawa, and Norimasa Nakamura. Collection and assembly of data: Masato Kobayashi and Ryota Chijimatsu, HY, and NN. Final approval of the article: Masato Kobayashi, Ryota Chijimatsu, David A. Hart, Shuichi Hamamoto, Fumiko Yano, Taku Saito, Kazunori Shimomura, Wataru Ando, Ung-il Chung, Sakae Tanaka, Hideki Yoshikawa, and Norimasa Nakamura.
Supporting Information
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term3149-sup-0001-suppl-data.xlsx9.7 KB | Supplementary Material |
term3149-sup-0002-fig_s1.tif123.8 KB | Supplementary Material |
term3149-sup-0003-fig_s2.tif2 MB | Supplementary Material |
term3149-sup-0004-fig_s3.tif3.2 MB | Supplementary Material |
term3149-sup-0005-fig_s4.tif7.3 MB | Supplementary Material |
term3149-sup-0006-suppl-data.xlsx71.2 KB | Supplementary Material |
term3149-sup-0007-suppl-data.xlsx228.1 KB | Supplementary Material |
term3149-sup-0008-fig_s5.tif4.5 MB | Supplementary Material |
term3149-sup-0009-fig_s6.tif972.5 KB | Supplementary Material |
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