Enhancement of chondrogenic differentiation supplemented by a novel small compound for chondrocyte-based tissue engineering

Abstract

Purpose: Chondrocyte-based tissue engineering has been a promising option for the treatment of cartilage lesions. In previous literature, TD198946 has been shown to promote chondrogenic differentiation which could prove useful in cartilage regeneration therapies. Our study aimed to investigate the effects of TD198946 in generating engineered cartilage using dedifferentiated chondrocyte-seeded collagen scaffolds treated with TD198946. Methods: Articular chondrocytes were isolated from mini pig knees and expanded in 2-dimensional cell culture and subsequently used in the experiments. 3-D pellets were then cultured for two weeks. Cells were also cultured in a type I collagen scaffolds for four weeks. Specimens were cultured with TD198946, BMP-2, or both in combination. Outcomes were determined by gene expression levels of RUNX1, SOX9, ACAN, COL1A1, COL2A1 and COL10A1, the glycosaminoglycan content, and characteristics of histology and immunohistochemistry. Furthermore, the maturity of the engineered cartilage cultured for two weeks was evaluated through subcutaneous implantation in nude mice for four weeks. Results: Addition of TD198946 demonstrated the upregulation of gene expression level except for ACAN, type II collagen and glycosaminoglycan synthesis in both pellet and 3D scaffold cultures. TD198946 and BMP-2 combination cultures showed higher chondrogenic differentiation than TD198946 or BMP-2 alone. The engineered cartilage maintained its extracellular matrices for four weeks post implantation. In contrast, engineered cartilage treated with either TD198946 or BMP-2 alone was mostly absorbed. Conclusions: Our results indicate that TD198946 could improve quality of engineered cartilage by redifferentiation of dedifferentiated chondrocytes pre-implantation and promoting collagen and glycosaminoglycan synthesis.

Enhanced chondrogenic differentiation of iPS cell-derived mesenchymal stem/stromal cells via neural crest cell induction for hyaline cartilage repair

“…Here, we show for the first time the chondrogenic potential of TD on iPSC-derived MSCs. Although the exact mechanism by which TD supports chondrogenesis is unclear, TD has been reported to upregulate Runx1 , Sox9 , and Col2a1 ( Yano et al, 2013a ; Hamamoto et al, 2020 ). T1-iMSCs treated with 100 nM TD showed upregulation of SOX9 , ACAN , and COL2A1 as well as increased GAG production without a noticeable effect on hypertrophy.…”

Studies of Articular Cartilage Repair from 2009 to 2018: A Bibliometric Analysis of Articles

“…Tissue engineering technology has been one of the top research focuses in the field of articular cartilage repair 23 . Stem cells and tissue scaffold were two subtopics occupying the primary portion of the overall publication numbers in the field of cartilage repair 24,25 .…”

The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells

“…Thus, we considered that the expression of COL2A1 is not a direct target of TD-198946. TD-198946 synergistically increases the expression of COL2A1 when combined with transforming growth factor-β3 or bone morphogenetic protein-2 17 , 19 . Further research is needed to explore the optimal combinations of TD-198946 and growth factors that enhance the expression of COL2A1 in hNPCs.…”