Evidence that TD-198946 enhances the chondrogenic potential of human synovium-derived stem cells through the NOTCH3 signaling pathway

Masato Kobayashi, Ryota Chijimatsu, David A. Hart, Shuichi Hamamoto, George Jacob, Fumiko Yano, Taku Saito, Kazunori Shimomura, Wataru Ando, Ung il Chung, Sakae Tanaka, Hideki Yoshikawa, Norimasa Nakamura

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)103-115
Number of pages13
JournalJournal of Tissue Engineering and Regenerative Medicine
Volume15
Issue number2
DOIs
Publication statusPublished - Feb 2021
Externally publishedYes

Keywords

  • chemicalcompound
  • chondrogenesis
  • human synovium
  • Notch signaling
  • stem cells

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biomaterials
  • Biomedical Engineering

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