Effect of the small compound TD-198946 on glycosaminoglycan synthesis and transforming growth factor β3-associated chondrogenesis of human synovium-derived stem cells in vitro

Ryota Chijimatsu, Fumiko Yano, Taku Saito, Masato Kobayashi, Shuichi Hamamoto, Takashi Kaito, Junichi Kushioka, David A. Hart, Ung il Chung, Sakae Tanaka, Hideki Yoshikawa, Norimasa Nakamura

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

As an alternative to chondrocytes-based cartilage repair, stem cell-based therapies have been investigated. Specifically, human synovium-derived stem cells (hSSCs) are a promising cell source based on their highly capacities for chondrogenesis, but some methodological improvements are still required towards optimal cartilage regeneration. Recently, a small compound, TD-198946, was reported to promote chondrogenesis of several stem cells, but the effect on hSSCs is still unknown. This study aimed to examine the effects of TD-198946 on chondrocyte differentiation and cartilaginous tissue formation with hSSCs. A range of concentrations of TD-198946 were examined in chondrogenic cultures of hSSC-derived cell pellets. The effect of TD-198946 on glycosaminoglycan (GAG) production, chondrocyte marker expression, and cartilaginous tissue formation was assessed. At concentrations >1 nM, TD-198946 dose-dependently enhanced GAG production, particularly hyaluronan, whereas chondrocyte differentiation was not impacted. When combined with transforming growth factor β3 (TGFβ3), TD-198946 promoted chondrocyte differentiation and production of cartilaginous matrices at doses <1 nM as judged by SOX9, S100, and type 2 collagen upregulation. Conversely, doses >1 nM TD-198946 attenuated TGFβ3-associated chondrocyte differentiation, but aggrecan was efficiently produced at 1 to 10 nM TD-198946 as judged by safranin O staining. Thus, TD-198946 exhibited different dose ranges for either GAG synthesis or chondrocyte differentiation. Regarding use of TD-198946 for in vitro engineering of cartilage, cartilaginous particles rich in type 2 collagen and GAG were predominately created with TGFβ3 + 0.25 nM TD-198946. These studies have demonstrated that TD-198946 synergistically enhances chondrogenesis of hSSCs in a unique dose range, and such findings may provide a novel strategy for stem cell-based cartilage therapy.

Original languageEnglish
Pages (from-to)446-458
Number of pages13
JournalJournal of Tissue Engineering and Regenerative Medicine
Volume13
Issue number3
DOIs
Publication statusPublished - Mar 2019
Externally publishedYes

Keywords

  • chemical compound
  • chondrogenesis
  • engineered cartilage
  • glycosaminoglycan
  • hyaluronan
  • synovium-derived stem cells

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biomaterials
  • Biomedical Engineering

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