Cell-sheet technology combined with a thienoindazole derivative small compound TD-198946 for cartilage regeneration.
Cell-sheet technology combined with a thienoindazole derivative small compound TD-198946 for cartilage regeneration.
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DOI：
10.1016/j.biomaterials.2013.04.008
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发表时间：
2013-07
期刊：
影响因子：
14
通讯作者：
Fumiko Yano;H. Hojo;Shinsuke Ohba;Taku Saito;Muneki Honnami;M. Mochizuki;T. Takato;H. Kawaguchi;U. Chung
中科院分区：
文献类型：
--
作者：
Fumiko Yano;H. Hojo;Shinsuke Ohba;Taku Saito;Muneki Honnami;M. Mochizuki;T. Takato;H. Kawaguchi;U. Chung
关节软骨是一种永久性组织，自我再生能力差。因此，软骨再生治疗的组织工程方法可以极大地推进软骨变性和/或缺损患者的当前治疗选择。成功的组织工程方法不仅需要诱导软骨分化，而且还需要抑制随后的软骨内骨化和软骨细胞去分化。我们先前报道，将噻吩并吲唑衍生物TD-198946直接注射到小鼠膝关节中可阻止骨关节炎的进展;该化合物诱导软骨形成分化，但不促进软骨内骨化。在本研究中，我们将TD-198946应用于基于细胞的软骨重建模型，利用细胞片技术。通过在温度响应性培养皿上用TD-198946培养小鼠和犬肋软骨细胞和人间充质干细胞来生成软骨细胞片层。然后，移植的细胞片被成功地用于促进永久性软骨的重建，在小鼠和犬的膝关节软骨缺损中没有软骨细胞肥大的证据。因此，TD-198946是基于细胞的软骨重建疗法的有希望的候选者，使我们能够避免围绕使用支架或细胞因子刺激再生的任何担忧。
Articular cartilage is a permanent tissue, with poor self-regenerative capacity. Consequently, a tissue engineering approach to cartilage regenerative therapy could greatly advance the current treatment options for patients with cartilage degeneration and/or defects. A successful tissue engineering approach would require not only induction of chondrogenic differentiation, but also suppression of subsequent endochondral ossification and chondrocyte dedifferentiation. We previously reported that direct injection of the thienoindazole derivative, TD-198946, into the knee joints of mice halted the progression of osteoarthritis; the compound induced chondrogenic differentiation without promoting endochondral ossification. In the present study, we applied TD-198946 to a cell-based cartilage reconstruction model, taking advantage of the cell-sheet technology. Cartilaginous cell-sheets were generated by culturing mouse and canine costal chondrocytes and human mesenchymal stem cells with TD-198946 on temperature-responsive dishes. The transplanted cell-sheets were then successfully used to promote the reconstruction of permanent cartilage, with no evidence of chondrocyte hypertrophy in the knee articular cartilage defects created in mice and canines. Thus, TD-198946 is a promising candidate for cell-based cartilage reconstruction therapies, enabling us to avoid any concern surrounding the use of scaffolds or cytokines to stimulate regeneration.