Tff2定义了缺乏再生潜力并且对Kras驱动的癌变具有保护作用的胰腺小泡祖细胞。
Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis.
发表日期：2023 Aug 03
作者：
Zhengyu Jiang, Feijing Wu, Pasquale Laise, Tanaka Takayuki, Fu Na, Woosook Kim, Hiroki Kobayashi, Wenju Chang, Ryota Takahashi, Giovanni Valenti, Masaki Sunagawa, Ruth A White, Marina Macchini, Bernhard W Renz, Moritz Middelhoff, Yoku Hayakawa, Zinaida A Dubeykovskaya, Xiangtian Tan, Timothy H Chu, Karan Nagar, Yagnesh Tailor, Bryana R Belin, Akanksha Anand, Samuel Asfaha, Michael O Finlayson, Alina C Iuga, Andrea Califano, Timothy C Wang
来源：
Cell Stem Cell
摘要：
虽然成人胰腺干细胞不被认为存在，但现在人们认识到腺泡间贮藏了包括组织修复的旁分化的前体细胞在内的前体细胞。在这里，我们研究了由三叶属因子2 (Tff2) 表达标记的胰腺腺泡细胞群体。长期谱系追踪和单细胞RNA测序(Tff2-DTR-CreERT2标靶细胞)对Tff2+细胞进行了定义，这些细胞构成了正常稳态的移行扩增的前体细胞(TAP)群体。在急性和慢性损伤后，与FPs有所区别的Tff2+细胞经历减少，但最终会再生。在基线状态下，致癌性KrasG12D经目标化的Tff2+细胞对PDAC的启动具有抵抗性。然而，在胰腺炎和癌症干/前体细胞的状态中，KrasG12D在Tff2+细胞中激活导致存活和克隆扩张。在Mist1+腺泡或Dclk1+ FP细胞中，在KrasG12D激活之前选择性消除Tff2+细胞导致增强的肿瘤发生，这可部分通过腺病毒Tff2治疗来挽救。综上所述，Tff2定义了一种胰腺TAP群体，能对抗Kras驱动的癌变。版权所有© 2023年Elsevier Inc. 保留所有权利。
While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreERT2-targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2+ cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic KrasG12D-targeted Tff2+ cells are resistant to PDAC initiation. However, KrasG12D activation in Tff2+ cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2+ cells prior to KrasG12D activation in Mist1+ acinar or Dclk1+ FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.Copyright © 2023 Elsevier Inc. All rights reserved.