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Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis.
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.
  • Jiang Z; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Wu F; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
  • Laise P; Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; DarwinHealth Inc., New York, NY, USA.
  • Takayuki T; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Na F; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.
  • Kim W; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Kobayashi H; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Chang W; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Takahashi R; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Valenti G; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Sunagawa M; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • White RA; Division of Hematology and Oncology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Macchini M; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Renz BW; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of General, Visceral, and Transplantation Surgery, LMU University Hospital, LMU Munich, Germany.
  • Middelhoff M; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Division of Digestive and Liver Diseases, CU and Klinikum rechts der Isar, Technical University, Munich, Germany.
  • Hayakawa Y; Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.
  • Dubeykovskaya ZA; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Tan X; Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Chu TH; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Nagar K; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Tailor Y; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Belin BR; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Anand A; Division of Digestive and Liver Diseases, Department of Medicine and Department of Gastroenterology II, Klinikum rechts der Isar, Technical University, Munich, Germany.
  • Asfaha S; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • Finlayson MO; Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Iuga AC; Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Califano A; Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; DarwinHealth Inc., New York, NY, USA.
  • Wang TC; Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address: tcw21@columbia.edu.
Cell Stem Cell ; 30(8): 1091-1109.e7, 2023 08 03.
Article en En | MEDLINE | ID: mdl-37541213
ABSTRACT
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Límite: Humans Idioma: En Año: 2023 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Límite: Humans Idioma: En Año: 2023 Tipo del documento: Article