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Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury.
Ma, Zhibo; Lytle, Nikki K; Chen, Bob; Jyotsana, Nidhi; Novak, Sammy Weiser; Cho, Charles J; Caplan, Leah; Ben-Levy, Olivia; Neininger, Abigail C; Burnette, Dylan T; Trinh, Vincent Q; Tan, Marcus C B; Patterson, Emilee A; Arrojo E Drigo, Rafael; Giraddi, Rajshekhar R; Ramos, Cynthia; Means, Anna L; Matsumoto, Ichiro; Manor, Uri; Mills, Jason C; Goldenring, James R; Lau, Ken S; Wahl, Geoffrey M; DelGiorno, Kathleen E.
Afiliación
  • Ma Z; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
  • Lytle NK; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
  • Chen B; Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Jyotsana N; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
  • Novak SW; Waitt Advanced Biophotonics Center, Salk Insitute for Biological Studies, La Jolla, California.
  • Cho CJ; Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas.
  • Caplan L; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
  • Ben-Levy O; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
  • Neininger AC; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
  • Burnette DT; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
  • Trinh VQ; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Tan MCB; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Patterson EA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
  • Arrojo E Drigo R; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
  • Giraddi RR; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
  • Ramos C; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
  • Means AL; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Matsumoto I; Monell Chemical Senses Center, Philadelphia, Pennsylvania.
  • Manor U; Waitt Advanced Biophotonics Center, Salk Insitute for Biological Studies, La Jolla, California.
  • Mills JC; Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas.
  • Goldenring JR; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Department of Surgery, Vanderbilt University Medical Center, Na
  • Lau KS; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt Univer
  • Wahl GM; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
  • DelGiorno KE; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt Univer
Gastroenterology ; 162(2): 604-620.e20, 2022 02.
Article en En | MEDLINE | ID: mdl-34695382
ABSTRACT
BACKGROUND &

AIMS:

Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression.

METHODS:

Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate post-injury. Transcripts of more than 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared with gastric metaplasia, KrasG12D-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. KrasG12D was expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining.

RESULTS:

scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison with KrasG12D-induced ADM identifies populations associated with disease progression. Activation of KrasG12D expression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype.

CONCLUSIONS:

Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. KrasG12D expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Conductos Pancreáticos / Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Células Acinares / Metaplasia Límite: Humans Idioma: En Año: 2022 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Conductos Pancreáticos / Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Células Acinares / Metaplasia Límite: Humans Idioma: En Año: 2022 Tipo del documento: Article