Tuft Cell Formation Reflects Epithelial Plasticity in Pancreatic Injury: Implications for Modeling Human Pancreatitis
Tuft Cell Formation Reflects Epithelial Plasticity in Pancreatic Injury: Implications for Modeling Human Pancreatitis
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DOI：
10.3389/fphys.2020.00088
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发表时间：
2020-02-14
影响因子：
4
通讯作者：
Wahl, Geoffrey M.
中科院分区：
文献类型：
--
作者：
DelGiorno, Kathleen E.;Naeem, Razia F.;Wahl, Geoffrey M.
慢性胰腺炎是胰腺导管腺癌（PDA）发展的已知风险因素，是一种严重、广泛的医学疾病，其特征为炎症、纤维化和腺泡至导管化生（ADM）。ADM是一种细胞类型的转分化事件，其中胰腺腺泡细胞在损伤或致癌突变的条件下变成导管样。在这里，我们表明，慢性胰腺炎和ADM在遗传野生型小鼠的结果在形成一个显着的群体的化学感受簇细胞。胰腺炎簇细胞的转录组学分析鉴定炎性介质的表达，这与簇细胞在损伤进展和/或消退中的作用一致。虽然与其他器官和疾病系统中的簇状细胞群相似，但我们确定了一些关键差异，这些差异表明了特定于环境的簇状细胞功能。我们评估了七种不同的小鼠品系的簇状细胞形成在慢性损伤的反应，并确定了显着的异质性，反映不同的倾向，上皮可塑性菌株之间。这些结果在胰腺炎中上皮可塑性和异质性的作用方面具有有趣的意义，并突出了在模拟人类疾病时小鼠品系选择的重要性。
Chronic pancreatitis, a known risk factor for the development of pancreatic ductal adenocarcinoma (PDA), is a serious, widespread medical condition characterized by inflammation, fibrosis, and acinar to ductal metaplasia (ADM). ADM is a cell type transdifferentiation event where pancreatic acinar cells become ductal-like under conditions of injury or oncogenic mutation. Here, we show that chronic pancreatitis and ADM in genetically wild type mice results in the formation of a significant population of chemosensory tuft cells. Transcriptomic analyses of pancreatitis tuft cells identify expression of inflammatory mediators, consistent with a role for tuft cells in injury progression and/or resolution. Though similar to tuft cell populations in other organs and disease systems, we identified a number of key differences that suggest context-specific tuft cell functions. We evaluated seven different mouse strains for tuft cell formation in response to chronic injury and identified significant heterogeneity reflecting varying proclivity for epithelial plasticity between strains. These results have interesting implications in the role of epithelial plasticity and heterogeneity in pancreatitis and highlight the importance of mouse strain selection when modeling human disease.