Piezo1-mediated stellate cell activation causes pressure-induced pancreatic fibrosis in mice.
Piezo1-mediated stellate cell activation causes pressure-induced pancreatic fibrosis in mice.
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DOI：
10.1172/jci.insight.158288
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发表时间：
2022-04-22
期刊：
影响因子：
8
通讯作者：
Liddle, Rodger A.
中科院分区：
文献类型：
--
作者：
Swain, Sandip M.;Romac, Joelle M-J;Vigna, Steven R.;Liddle, Rodger A.
胰腺纤维化是慢性胰腺炎的并发症，也是胰腺癌的显著特征。胰腺纤维化常见于胰管梗阻时间较长的患者，这会使胰腺内压力升高。我们在这里展示了胰管压力增加导致纤维化，并描述了压力增加细胞外基质蛋白沉积和纤维化的机制。我们发现胰腺星状细胞(PSCs)是纤维化中细胞外基质蛋白的来源，它表达机械激活的离子通道Piezo1。通过增加细胞内钙离子、机械应力或Piezo1激动剂Yoda1激活的PSCs，表现为核周脂肪滴丢失，转化生长因子-β1、纤维连接蛋白和I型胶原表达增加。这些作用被Piezo1抑制剂GsMTx4阻断，并且在星状细胞中Piezo1有条件基因缺失的小鼠的PSCs中不存在，就像胰管结扎诱导的纤维化一样。虽然TRPV4被认为具有直接的机械传感特性，但我们发现来自TRPV4-KO小鼠的PSCs可以被保护而不受Yoda1触发的激活。此外，缺乏TRPV4的小鼠可以免受胰管结扎诱导的纤维化的影响。因此，胰腺内的高压刺激Piezo1通道的开放，随后TRPV4的激活导致星状细胞激活和压力诱导的慢性胰腺炎和纤维化。
Pancreatic fibrosis is a complication of chronic pancreatitis and is a prominent feature of pancreatic cancer. Pancreatic fibrosis is commonly observed in patients with prolonged pancreatic duct obstruction, which elevates intrapancreatic pressure. We show here that increased pancreatic duct pressure causes fibrosis and describes the mechanism by which pressure increases deposition of extracellular matrix proteins and fibrosis. We found that pancreatic stellate cells (PSCs), the source of the extracellular matrix proteins in fibrosis, express the mechanically activated ion channel Piezo1. By increasing intracellular calcium, mechanical stress or the Piezo1 agonist Yoda1-activated PSCs manifest by loss of perinuclear fat droplets and increased TGF-β1, fibronectin, and type I collagen expression. These effects were blocked by the Piezo1 inhibitor GsMTx4 and absent in PSCs from mice with conditional genetic deletion of Piezo1 in stellate cells, as was pancreatic duct ligation–induced fibrosis. Although TRPV4 has been proposed to have direct mechanosensing properties, we discovered that PSCs from Trpv4-KO mice were protected against Yoda1-triggered activation. Moreover, mice devoid of TRPV4 were protected from pancreatic duct ligation–induced fibrosis. Thus, high pressure within the pancreas stimulates Piezo1 channel opening, and subsequent activation of TRPV4 leads to stellate cell activation and pressure-induced chronic pancreatitis and fibrosis.
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影响因子：
5
作者：
Adapala RK;Thoppil RJ;Luther DJ;Paruchuri S;Meszaros JG;Chilian WM;Thodeti CK
通讯作者：
Thodeti CK
TRPV4和TRPA1的小分子双抑制剂，用于炎症和疼痛的衰减。
影响因子：
4.6
作者：
Kanju P;Chen Y;Lee W;Yeo M;Lee SH;Romac J;Shahid R;Fan P;Gooden DM;Simon SA;Spasojevic I;Mook RA;Liddle RA;Guilak F;Liedtke WB
通讯作者：
Liedtke WB
影响因子：
4.8
作者：
Berrout, Jonathan;Jin, Min;O'Neil, Roger G.
通讯作者：
O'Neil, Roger G.
影响因子：
4
作者：
Apte MV;Pirola RC;Wilson JS
通讯作者：
Wilson JS
影响因子：
24.5
作者：
Apte, MV;Haber, PS;Wilson, JS
通讯作者：
Wilson, JS