Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis
Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis
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DOI：
10.1016/j.stem.2023.07.002
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发表时间：
2023-08-03
期刊：
影响因子：
23.9
通讯作者：
Wang，Timothy C.
中科院分区：
文献类型：
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作者：
Jiang，Zhengyu;Wu，Feijing;Wang，Timothy C.
虽然成人胰腺干细胞被认为不存在，但现在人们意识到腺泡间有祖细胞，包括组织修复兼性祖细胞(FP)。在这里，我们研究了以三叶因子2(Tff2)表达为标志的胰腺腺泡细胞群。对Tff2-DTR-CreERT2靶向细胞的长期谱系追踪和单细胞RNA测序(scRNA-seq)分析定义了有助于正常内稳的运输放大祖细胞(TAP)群体。在急性和慢性损伤后，Tff2+细胞不同于FP，经历人口减少，但最终得到补充。在基线水平，致癌的KrasG12D靶向Tff2+细胞对PDAC启动具有抵抗力。然而，Tff2+细胞中KrasG12D的激活导致胰腺炎和癌症干/祖细胞样状态后的存活和克隆性扩张。在Mist1+腺泡细胞或Dclk1+FP细胞中，在KrasG12D激活之前选择性地消融Tff2+细胞可以增强肿瘤的形成，这可以用腺病毒Tff2治疗部分挽救。总而言之，Tff2定义了一个胰腺TAP群体，可以防止Kras驱动的致癌作用。
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 ofTff2-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, KrasG12Dactivation 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 KrasG12Dactivation 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.