Pharmacological activation of TAZ enhances osteogenic differentiation and bone formation of adipose-derived stem cells.
Pharmacological activation of TAZ enhances osteogenic differentiation and bone formation of adipose-derived stem cells.
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TAZ 的药理激活增强脂肪干细胞的成骨分化和骨形成
DOI：
10.1186/s13287-018-0799-z
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发表时间：
2018-03-07
影响因子：
7.5
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Zhu Y;Wu Y;Cheng J;Wang Q;Li Z;Wang Y;Wang D;Wang H;Zhang W;Ye J;Jiang H;Wang L
脂肪来源干细胞（ADSCs）是骨组织工程中一种有吸引力的细胞来源，在骨再生和缺损修复方面具有巨大潜力。含PDZ结合基序的转录共激活因子（TAZ）已被证明可调节间充质干细胞的成骨和成脂分化。然而，它在ADSCs分化过程中的作用以及在骨再生方面的治疗潜力尚未得到充分确定。
在体外ADSCs成骨分化过程中对TAZ的表达进行了检测。通过TAZ敲低（功能缺失）或强制过表达（功能获得）的方法来确定其在ADSCs成骨分化过程中的功能。使用TAZ的化学激活剂TM - 25659来确定在ADSCs中对TAZ进行药理激活是否能增强体外成骨分化以及在动物模型中的骨形成。还探讨了TAZ促进ADSCs成骨的分子机制。
在人ADSCs成骨分化过程中观察到TAZ表达增加。TAZ敲低导致ADSCs成骨分化受损，成脂分化增强。相反，强制TAZ过表达使体内成骨分化和骨再生增加，ADSCs成脂分化受损。其化学激活剂TM - 25659对TAZ的药理激活促进了ADSCs的成骨分化。值得注意的是，用TM - 25659对ADSCs进行短暂处理或腹腔注射TM - 25659显著增强了体内负载多孔β - TCP的ADSCs的骨再生。从机制上讲，TM - 25659暴露显著促进了TAZ的磷酸化和核转位，并增强了TAZ - Runx2复合物的组装。随后，TAZ - Runx2复合物进一步被招募到骨钙素启动子上，进而增强其转录。
我们的研究结果表明，TAZ是促进ADSCs向成骨细胞谱系分化的关键介质。对ADSCs中TAZ进行药理激活可能成为一种增强骨再生和修复的可行且有前景的方法。
本文的在线版本（10.1186/s13287 - 018 - 0799 - z）包含补充材料，授权用户可获取。
Adipose-derived stem cells (ADSCs) are an attractive cell source for bone tissue engineering and have great potential for bone regeneration and defect repair. The transcriptional coactivator with PDZ-binding motif (TAZ) has been demonstrated to modulate osteogenic and adipogenic differentiation of mesenchymal stem cells. However, its roles during ADSC differentiation and therapeutic potentials for bone regeneration have as yet not been well established. TAZ expression was measured during osteogenic differentiation of ADSCs in vitro. Both loss-of-function and gain-of-function approaches by TAZ knockdown or enforced overexpression were utilized to determine its functions during osteogenic differentiation of ADSCs. TM-25659, a chemical activator of TAZ, was used to determine whether pharmacological activation of TAZ in ADSCs enhanced osteogenic differentiation in vitro and bone formation in animal models. The molecular mechanisms underlying TAZ in promoting osteogenesis of ADSCs were also explored. Increased TAZ expression was observed during osteogenic differentiation of human ADSCs. TAZ knockdown resulted in compromised osteogenic differentiation and enhanced adipogenic differentiation of ADSCs. In contrast, enforced TAZ overexpression yielded increased osteogenic differentiation and bone regeneration in vivo, and impaired adipogenic differentiation of ADSCs. Pharmacological activation of TAZ by its chemical activator TM-25659 facilitated osteogenic differentiation of ADSCs. Noticeably, transient treatment of ADSCs with TM-25659 or intraperitoneal injection of TM-25659 significantly enhanced bone regeneration of ADSCs loaded with porous β-TCP in vivo. Mechanistically, TM-25659 exposure significantly promoted TAZ phosphorylation and nuclear translocation, and potentiated the assembly of the TAZ-Runx2 complex. Subsequently, the TAZ-Runx2 complex was further recruited to the promoter of osteocalcin and in turn enhanced its transcription. Our findings indicate that TAZ is a key mediator that promotes ADSC commitment to the osteoblast lineage. Pharmacological activation of TAZ in ADSCs might become a feasible and promising approach to enhance bone regeneration and repair. The online version of this article (10.1186/s13287-018-0799-z) contains supplementary material, which is available to authorized users.
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影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
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影响因子：
12.4
作者：
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DOI：
10.1016/j.jpba.2012.01.036
发表时间：
2012-04-07
影响因子：
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