Cell stem cell · 2023
Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Ошибки и ограничения
История · было → стало
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Jiang Zhengyu, Wu Feijing, Laise Pasquale, Takayuki Tanaka, Na Fu, Kim Woosook, Kobayashi Hiroki, Chang Wenju, Takahashi Ryota, Valenti Giovanni, Sunagawa Masaki, White Ruth A, Macchini Marina, Renz Bernhard W, Middelhoff Moritz, Hayakawa Yoku, Dubeykovskaya Zinaida A, Tan Xiangtian, Chu Timothy H, Nagar Karan, Tailor Yagnesh, Belin Bryana R, Anand Akanksha, Asfaha Samuel, Finlayson Michael O, Iuga Alina C, Califano Andrea, Wang Timothy C
Аннотация
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.