Quaking promotes the odontoblastic differentiation of human dental pulp stem cells
Quaking promotes the odontoblastic differentiation of human dental pulp stem cells
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震动促进人牙髓干细胞向成牙本质细胞分化
DOI：
10.1002/jcp.26561
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发表时间：
2018-09-01
影响因子：
5.6
通讯作者：
Chen, Zhi
中科院分区：
文献类型：
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作者：
Li, Shuchen;Lin, Chujiao;Chen, Zhi
人牙髓干细胞（hDPSC）的成牙本质细胞分化对于龋齿或损伤后修复性牙本质的形成至关重要。我们前期的研究表明，kruppel样因子4（KLF4）是促进hDPSCs成牙本质细胞分化的关键转录因子。对 KLF4 3-UTR 内 microRNA 结合位点的分析表明，RNA 结合蛋白 QKI 与 KLF4 共享最多的 microRNA，可能与 KLF4 一起充当有效的内源 RNA (ceRNA)。因此，我们假设 QKI 也可以促进成牙本质细胞分化。在这项研究中，我们发现QKI在小鼠体内成牙本质细胞分化和hDPSCs体外成牙本质细胞分化过程中上调。 hDPSCs中QKI的过表达或敲低会导致成牙本质细胞标记基因表达的增加或减少，表明其在成牙本质细胞分化中发挥积极作用。我们通过 hDPSC 中共享 miRNA 的相互作用进一步验证了 QKI 作为 KLF4 的关键 ceRNA。最后，我们发现，作为一种RNA结合蛋白，QKI蛋白可以结合并稳定牙本质唾液酸磷蛋白（DSPP）mRNA，从而导致DSP蛋白的积累增加。综上所述，我们的研究表明，QKI 通过充当 KLF4 的 ceRNA 和 DSPP mRNA 的结合蛋白来稳定其水平，从而促进 hDPSC 的成牙本质细胞分化。 QKI 的这两种机制将共同积极调节下游途径，从而增强成牙本质细胞的分化。
Odontoblastic differentiation of human dental pulp stem cells (hDPSCs) is essential for the formation of reparative dentin after dental caries or injury. Our previous studies have demonstrated that kruppel-like factor 4 (KLF4) is a critical transcription factor that promotes the odontoblastic differentiation of hDPSCs. Analysis of the microRNA binding sites within the 3-UTR of KLF4 revealed that QKI, an RNA-binding protein, shared the most microRNAs with KLF4, presumably served as a competent endogenous RNA (ceRNA) with KLF4. Thus, we hypothesized QKI could also promote odontoblastic differentiation. In this study, we found QKI was up-regulated during mouse odontoblast differentiation in vivo and hDPSCs odontoblastic differentiation in vitro. Overexpression or knockdown of QKI in hDPSCs led to the increase or decrease of odontoblast marker genes' expressions, indicating its positive role in odontoblastic differentiation. We further validated that QKI served as a key ceRNA of KLF4 via interaction of the shared miRNAs in hDPSCs. Last, we found that, as an RNA binding protein, QKI protein could bind to, and stabilize dentin sialophosphoprotein (DSPP) mRNA, resulting in the augmented accumulation of DSP protein. Taken together, our study indicates that QKI promotes the odontoblastic differentiation of hDPSCs by acting as a ceRNA of KLF4 and as a binding protein of DSPP mRNA to stabilize its level. These two mechanisms of QKI will together positively regulate the downstream pathways and hence potentiate odontoblastic differentiation.