Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice

Gastroenterology. 2011 Oct;141(4):1463-72. doi: 10.1053/j.gastro.2011.06.045. Epub 2011 Jun 24.

Abstract

Background & aims: Progression of diseases of the exocrine pancreas, which include pancreatitis and cancer, is associated with increased levels of cell stress. Pancreatic acinar cells are involved in development of these diseases and, because of their high level of protein output, they require an efficient, unfolded protein response (UPR) that mediates recovery from endoplasmic reticulum (ER) stress following the accumulation of misfolded proteins.

Methods: To study recovery from ER stress in the exocrine organ, we generated mice with conditional disruption of Xbp1 (a principal component of the UPR) in most adult pancreatic acinar cells (Xbp1fl/fl). We monitored the effects of constitutive ER stress in the exocrine pancreas of these mice.

Results: Xbp1-null acinar cells underwent extensive apoptosis, followed by a rapid phase of recovery in the pancreas that included expansion of the centroacinar cell compartment, formation of tubular complexes that contained Hes1- and Sox9-expressing cells, and regeneration of acinar cells that expressed Mist1 from the residual, surviving Xbp1+ cell population.

Conclusions: XBP1 is required for homeostasis of acinar cells in mice; ER stress induces a regenerative response in the pancreas that involves acinar and centroacinar cells, providing the needed capacity for organ recovery from exocrine pancreas disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Lineage
  • Cell Proliferation*
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Homeodomain Proteins / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Pancreas, Exocrine / metabolism*
  • Pancreas, Exocrine / pathology
  • Pancreatic Diseases / genetics
  • Pancreatic Diseases / metabolism*
  • Pancreatic Diseases / pathology
  • Protein-Serine-Threonine Kinases / metabolism
  • Regeneration*
  • Regulatory Factor X Transcription Factors
  • SOX9 Transcription Factor / metabolism
  • Stress, Physiological
  • Time Factors
  • Transcription Factor HES-1
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Unfolded Protein Response
  • X-Box Binding Protein 1

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlha15 protein, mouse
  • DNA-Binding Proteins
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Membrane Proteins
  • Regulatory Factor X Transcription Factors
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Transcription Factor HES-1
  • Transcription Factors
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Ern2 protein, mouse
  • Protein-Serine-Threonine Kinases