Disruption of myofibroblastic Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression.
Disruption of myofibroblastic Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression.
复制标题
肌成纤维细胞 Notch 信号传导的破坏可通过调节纤维化进展和消退来减轻肝纤维化
DOI：
10.7150/ijbs.60056
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发表时间：
2021
影响因子：
9.2
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Yue Z;Jiang Z;Ruan B;Duan J;Song P;Liu J;Han H;Wang L
肝肌成纤维细胞（MFs）的表型转化参与了肝纤维化进展和消退的全过程。Notch信号已被证实可调节纤维化。在本研究中，我们通过检测MFs中的Notch信号读数，发现MFs中的Notch信号分别随着肝纤维化的进展和消退而过度激活和抑制。此外，我们在Sm22αCreER-RBPjflox/flox小鼠（RBPjMF-KO）中特异性灭活了MFs中的Notch信号，并发现MFs特异性下调Notch信号可显著缓解ccl4诱导的肝纤维化进展和消退过程。在肝纤维化进展过程中，MFs特异性阻断Notch信号抑制hsc对MFs的激活，增加MMPs的表达，从而减少ECM的沉积。在纤维化消退过程中，阻断Notch信号通路可增加HGF的表达，促进肝细胞增殖，上调促凋亡因子Ngfr和Septin4的表达，诱导MFs凋亡，从而加速纤维化逆转。总的来说，mfs特异性的Notch信号破坏通过调节纤维化的进展和消退来减轻肝纤维化，这表明了一种有希望的肝纤维化治疗策略。
The phenotypic transformation of hepatic myofibroblasts (MFs) is involved in the whole process of the progression and regression of liver fibrosis. Notch signaling has been demonstrated to modulate the fibrosis. In this study, we found that Notch signaling in MFs was overactivated and suppressed with the progression and regression of hepatic fibrosis respectively, by detecting Notch signaling readouts in MFs. Moreover, we inactivated Notch signaling specifically in MFs with Sm22αCreER-RBPjflox/flox mice (RBPjMF-KO), and identified that MFs-specific down-regulation of Notch signaling significantly alleviated CCl4-induced liver fibrosis during the progression and regression. During the progression of liver fibrosis, MFs-specific blockade of Notch signaling inhibited the activation of HSCs to MFs and increases the expression of MMPs to reduce the deposition of ECM. During the regression of fibrosis, blocking Notch signaling in MFs increased the expression of HGF to promote proliferation in hepatocytes and up-regulated the expression of pro-apoptotic factors, Ngfr and Septin4, to induce apoptosis of MFs, thereby accelerating the reversal of fibrosis. Collectively, the MFs-specific disruption of Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression, which suggests a promising therapeutic strategy for liver fibrosis.
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影响因子：
29.4
作者：
Issa, R;Zhou, XY;Iredale, JP
通讯作者：
Iredale, JP
DOI：
10.1073/pnas.90.16.7859
发表时间：
1993-08-15
影响因子：
11.1
作者：
BENEDETTI, M;LEVI, A;CHAO, MV
通讯作者：
CHAO, MV
影响因子：
13.5
作者：
Kendall, Timothy J.;Hennedige, Selina;Iredale, John P.
通讯作者：
Iredale, John P.
影响因子：
13.5
作者：
Geisler, Fabian;Strazzabosco, Mario
通讯作者：
Strazzabosco, Mario
内皮Notch激活重塑肝窦内皮细胞的血管分泌，加剧小鼠肝纤维化并钝化再生
DOI：
10.1002/hep.29834
发表时间：
2018-08
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Duan JL;Ruan B;Yan XC;Liang L;Song P;Yang ZY;Liu Y;Dou KF;Han H;Wang L
通讯作者：
Wang L