Hedgehog Signaling Demarcates a Niche of Fibrogenic Peribiliary Mesenchymal Cells.
Hedgehog Signaling Demarcates a Niche of Fibrogenic Peribiliary Mesenchymal Cells.
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DOI：
10.1053/j.gastro.2020.03.075
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发表时间：
2020-08
期刊：
影响因子：
29.4
通讯作者：
Schwartz RE
中科院分区：
文献类型：
--
作者：
Gupta V;Gupta I;Park J;Bram Y;Schwartz RE
响应于组织损伤，基质细胞分泌重塑组织并导致纤维化的细胞外基质（ECM）组分。实质星状细胞是肝细胞和胆汁淤积性损伤模型中纤维化的主要贡献者。肝脏包括不同的，异质的隔间;这些隔间内的基质细胞可能具有独特的身份和区域功能。汇管区包含胆管，其被通常称为汇管区成纤维细胞的基质细胞包围。我们研究了这些细胞对肝损伤的贡献。我们用Gli 1：CreERT 2; Rosa 26：lox-STOP-lox-tdTomato小鼠进行了研究。小鼠进行胆管结扎或喂食3，5-二乙氧羰基-1，4-二氢可力丁以诱导胆汁淤积性损伤或给予CCL 4以诱导肝纤维化。收集肝组织并通过组织学和免疫荧光分析，分离间充质细胞。我们进行了谱系追踪实验，以确定胆汁淤积和肝细胞损伤后胆管周围间充质细胞（PMC）的命运。我们使用细胞分选，结合RNA测序，分离星状细胞和PMC，并确定每个群体中细胞身份的决定因素。肝组织从患有原发性硬化性胆管炎、酒精性肝病、非酒精性脂肪性肝炎或无疾病的患者获得，并通过定量逆转录PCR进行分析。Gli 1是围绕胆管树的间充质细胞的标记，但不是Hering管的上皮细胞。谱系追踪Gli 1 + PMC增殖，并获得了肌成纤维细胞表型后胆汁淤积性损伤; Gli 1 + PMC被发现只围绕主管道的门脉道，但不是上皮细胞的小管反应，而不是包裹星状细胞。与星状细胞相比，Gli 1 + PMC表达不同的基因子集，包括作为活跃的hedgehog信号传导的标志物的基因、Osr 1（编码转录因子）和ECM相关基因。hedgehog信号的丢失降低了Osr 1和PMC特异性ECM基因的表达。与对照肝组织相比，肝病患者的肝组织中定义PMC身份的基因表达增加。在小鼠的谱系追踪研究中，我们发现Gli 1 + PMC是基质细胞的一个子集，其特征在于活跃的刺猬信号，增殖，获得肌成纤维细胞表型，并围绕胆道树响应胆汁淤积性损伤。
In response to tissue injury, stromal cells secrete extracellular matrix (ECM) components that remodel the tissue and lead to fibrosis. Parenchymal stellate cells are the primary contributors to fibrosis in models of hepatocellular and cholestatic injury. The liver comprises different, heterogenous compartments; stromal cells within those compartments might have unique identities and regional functions. The portal tract contains the bile duct, which is surrounded by stromal cells often called portal fibroblasts. We investigated the contributions of these cells to hepatic injury. We performed studies with Gli1:CreERT2; Rosa26:lox-STOP-lox-tdTomato mice. Mice underwent bile duct ligation or were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine to induce cholestatic injury or were given CCL4 to induce liver fibrosis. Liver tissues were collected and analyzed by histology and immunofluorescence, and mesenchymal cells were isolated. We performed lineage tracing experiments to determine the fates of peribiliary mesenchymal cells (PMCs) that surround the bile duct after cholestatic and hepatocellular injury. We used cell sorting, combined with RNA- sequencing, to isolate stellate cells and PMCs, and identified determinants of cell identity within each population. Liver tissues were obtained from patients with primary sclerosing cholangitis, alcoholic liver disease, nonalcoholic steatohepatitis, or without disease and analyzed by quantitative reverse transcription PCR. Gli1 was a marker of mesenchymal cells that surround the biliary tree, but not epithelial cells of the canals of Hering. Lineage-traced Gli1+ PMCs proliferated and acquired a myofibroblast phenotype after cholestatic injury; Gli1+ PMCs were found only surrounding the main duct of a portal tract, but not the epithelial cells of the ductular reaction, which were instead encased by stellate cells. Compared with stellate cells, Gli1+ PMCs expressed a different subset of genes, including genes that are markers of active hedgehog signaling, Osr1 (encodes a transcription factor), and ECM-related genes. Loss of hedgehog signaling reduced expression of Osr1 and PMC-specific ECM genes. Liver tissues from patients with liver disease had increased expression of genes that define PMC identity, compared with control liver tissues. In lineage-tracing studies of mice, we found that Gli1+ PMCs are a subset of stromal cells characterized by active hedgehog signaling that proliferate, acquire a myofibroblast phenotype, and surround the biliary tree in response to cholestatic injury.
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