Basic fibroblast growth factor reduces scar by inhibiting the differentiation of epidermal stem cells to myofibroblasts via the Notch1/Jagged1 pathway.
Basic fibroblast growth factor reduces scar by inhibiting the differentiation of epidermal stem cells to myofibroblasts via the Notch1/Jagged1 pathway.
复制标题
碱性成纤维细胞生长因子通过 Notch1/Jagged1 途径抑制表皮干细胞向肌成纤维细胞的分化，从而减少疤痕
DOI：
10.1186/s13287-017-0549-7
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发表时间：
2017-05-16
影响因子：
7.5
通讯作者：
Xie J
中科院分区：
文献类型：
--
作者：
Wang P;Shu B;Xu Y;Zhu J;Liu J;Zhou Z;Chen L;Zhao J;Liu X;Qi S;Xiong K;Xie J
碱性成纤维细胞生长因子在促进创面愈合、减少瘢痕形成中起重要作用，但其可能的分子机制尚不清楚。我们以前的研究发现，激活Notch1/Jagged1通路可以抑制表皮干细胞(ESCs)向肌成纤维细胞(MFB)的分化。方法体外分离培养新生SD大鼠(1~3日龄)胚胎干细胞，无血清培养，分为6组：碱性成纤维细胞生长因子组、碱性成纤维细胞生长因子 + SU5402组、碱性成纤维细胞生长因子 + DAPT组、碱性成纤维细胞生长因子 + SIJagged1组和对照组。SiJagged1组和bFGFRNAsiJagged1组中的Jagged1被小干扰 + 表达下调。采用流式细胞术、定量RT-PCR法和免疫印迹法检测胚胎干细胞标志物(CK15/CK10)、MFB标志物(α-SMA、I型胶原、III型胶原)和Notch1/Jagged1组分(Jagged1、Notch1、Hes1)的表达，以探讨其与ESC、Notch1/Jagged1信号通路的关系。体内实验采用兔耳瘢痕模型，观察创面愈合时间和瘢痕增生情况。苏木精-伊红染色和Masson染色评价创面愈合质量。采用免疫组织化学、免疫荧光和免疫印迹等方法检测ESC标志物、MFB标志物和Notch1/Jagged1组分的表达。结果体外实验表明，bFGF可显著上调ESC标志物和Notch1/Jagged1组分的表达，同时下调MFB标志物的表达。然而，当我们取消Jagged1或添加DAPT时，这些影响可以明显降低。同样，在体内实验中，bFGF还通过激活Notch1/Jagged1通路抑制兔ESCs向MFB的分化，从而改善创面愈合质量，显著减轻瘢痕。结论bFGF通过Notch1/Jagged1途径抑制ESCs向MFB的分化，从而抑制瘢痕的形成，为瘢痕的治疗提供了新的潜在方向。
BackgroundBasic fibroblast growth factor (bFGF) plays an important role in promoting wound healing and reducing scar, but the possible molecular mechanisms are still unclear. Our previous studies have found that activating the Notch1/Jagged1 pathway can inhibit the differentiation of epidermal stem cells (ESCs) to myofibroblasts (MFB). Herein, we document that bFGF reduces scar by inhibiting the differentiation of ESCs to MFB via activating the Notch1/Jagged1 pathway.MethodsIn in-vitro study, ESCs were isolated from 10 neonatal SD rats (1–3 days old), cultured in keratinocyte serum-free medium, and divided into six groups: bFGF group, bFGF + SU5402 group, bFGF + DAPT group, siJagged1 group, bFGF + siJagged1 group, and control group. Jagged1 of the ESCs in the siJagged1 group and bFGF + siJagged1 group was knocked down by small-interfering RNA transfection. Expression of ESC markers (CK15/CK10), MFB markers (α-SMA, Collagen I, Collagen III), and Notch1/Jagged1 components (Jagged1, Notch1, Hes1) was detected by FCM, qRT-PCR, and western blot analysis to study the relationships of bFGF, ESCs, and Notch1/Jagged1 pathway. In in-vivo study, the wound healing time and scar hyperplasia were observed on rabbit ear scar models. The quality of wound healing was estimated by hematoxylin and eosin staining and Masson staining. Expression of ESC markers, MFB markers and Notch1/Jagged1 components was elucidated by immunohistochemistry, immunofluorescence, and western blot analysis.ResultsThe in-vitro study showed that bFGF could significantly upregulate the expression of ESC markers and Notch1/Jagged1 components, while downregulating the expression of MFB markers at the same time. However, these effects could be obviously decreased when we knocked down Jagged1 or added DAPT. Similarly, in in-vivo study, bFGF also exhibited its functions in inhibiting the differentiation of rabbit ESCs to MFB by activating the Notch1/Jagged1 pathway, which improved the wound healing quality and alleviated scar significantly.ConclusionThese results provide evidence that bFGF can reduce scar by inhibiting the differentiation of ESCs to MFB via the Notch1/Jagged1 pathway, and present a new promising potential direction for the treatment of scar.