TD-198946 通过 NOTCH3 信号通路增强人滑膜干细胞成软骨潜能的证据,Journal of Tissue Engineering and Regenerative Medicine

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TD-198946 通过 NOTCH3 信号通路增强人滑膜干细胞成软骨潜能的证据
Journal of Tissue Engineering and Regenerative Medicine ( IF 3.1 ) Pub Date : 2020-11-10 , DOI: 10.1002/term.3149
Masato Kobayashi ₁ , Ryota Chijimatsu ₂ , David A Hart ₃ , Shuichi Hamamoto ₁ , George Jacob ₁ , Fumiko Yano ₂ , Taku Saito ₄ , Kazunori Shimomura ₁ , Wataru Ando ₁ , Ung-Il Chung ₅ , Sakae Tanaka ₄ , Hideki Yoshikawa ₁ , Norimasa Nakamura ₆

Affiliation

人类滑膜衍生干细胞 (hSSC) 是一种有吸引力的软骨修复细胞来源。目前，用于软骨再生的组织质量和技术还有改进的余地。据报道，一种小化合物 TD-198946 可增强 hSSC 的软骨形成诱导；然而，TD-198946 的其他应用，例如引发 hSSC 的细胞潜能，仍然未知。我们的研究旨在检查 TD-198946 预处理对 hSSC 的影响。在扩增培养过程中，HSSCs 在有或没有 TD-198946 的情况下培养 7 天，然后转化为补充有骨形态发生蛋白-2（BMP2）和/或转化生长因子β-3（TGFβ3）的三维颗粒培养物。根据 GAG 含量、组织学和软骨形成标记基因的表达水平评估培养物中的软骨形成。当 BMP2 和 TGFβ3 诱导软骨形成时，来自 TD-198946 预处理的 hSSC 的细胞沉淀显示出增强的软骨形成潜力。此外，使用 BMP2 和 TGFβ3 的组合，从 TD-198946 预处理的 hSSCs 有效生成软骨组织。微阵列分析显示，在 TD-198946 处理的 hSSC 中，NOTCH 通路相关基因及其靶基因显着上调，尽管单独的 TD-198946 没有上调软骨形成相关标志物。NOTCH 信号抑制剂的给药减弱了 TD-198946 的作用。因此，TD-198946 通过 NOTCH3 信号通路增强 hSSCs 的软骨形成潜力。这项研究首次证明了在 hSSC 的软骨形成过程中 NOTCH3 信号的逐渐激活。

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

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.

更新日期：2020-11-10

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