Growth Factor Independence-1 (Gfi1) Is Required for Pancreatic Acinar Unit Formation and Centroacinar Cell Differentiation

Xiaoling Qu; Pia Nyeng; Fan Xiao; Jorge Dorantes; Jan Jensen

doi:10.1016/j.jcmgh.2014.12.004

Growth Factor Independence-1 (Gfi1) Is Required for Pancreatic Acinar Unit Formation and Centroacinar Cell Differentiation

Cell Mol Gastroenterol Hepatol. 2014 Dec 26;1(2):233-247.e1. doi: 10.1016/j.jcmgh.2014.12.004. eCollection 2015 Mar.

Authors

Xiaoling Qu¹, Pia Nyeng², Fan Xiao³, Jorge Dorantes¹, Jan Jensen¹

Affiliations

¹ Cleveland Clinic, Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio.
² Cleveland Clinic, Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio; Danish Stem Cell Center, University of Copenhagen, Copenhagen, Denmark.
³ Cleveland Clinic, Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio; Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Abstract

Background & aims: The genetic specification of the compartmentalized pancreatic acinar/centroacinar unit is poorly understood. Growth factor independence-1 (Gfi1) is a zinc finger transcriptional repressor that regulates hematopoietic stem cell maintenance, pre-T-cell differentiation, formation of granulocytes, inner ear hair cells, and the development of secretory cell types in the intestine. As GFI1/Gfi1 is expressed in human and rodent pancreas, we characterized the potential function of Gfi1 in mouse pancreatic development.

Methods: Gfi1 knockout mice were analyzed at histological and molecular levels, including qRT-PCR, in situ hybridization, immunohistochemistry, and electron microscopy.

Results: Loss of Gfi1 impacted formation and structure of the pancreatic acinar/centroacinar unit. Histologic and ultrastructural analysis of Gfi1-null pancreas revealed specific defects at the level of pancreatic acinar cells as well as the centroacinar cells (CACs) in Gfi1^-/- mice when compared with wild-type littermates. Pancreatic endocrine differentiation, islet architecture, and function were unaffected. Organ domain patterning and the formation of ductal cells occurred normally during the murine secondary transition (E13.5-E14.5) in the Gfi1^-/- pancreas. However, at later gestational time points (E18.5), expression of cellular markers for CACs was substantially reduced in Gfi1^-/- mice, corroborated by electron microscopy imaging of the acinar/centroacinar unit. The reduction in CACs was correlated with an exocrine organ defect. Postnatally, Gfi1 deficiency resulted in severe pancreatic acinar dysplasia, including loss of granulation, autolytic vacuolation, and a proliferative and apoptotic response.

Conclusions: Gfi1 plays an important role in regulating the development of pancreatic CACs and the function of pancreatic acinar cells.

Keywords: BPL, Bauhinia purpurea lectin; BrdU, bromodeoxyuridine; CACs, centroacinar cells; Centroacinar Cells; Claudin 10; DIG, digoxigenin; EM, electron micrographs; Gfi1, growth factor independence-1; Growth Factor Independence-1 (Gfi1); PBS, phosphate-buffered saline; SD, standard deviation; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; TipPC, tip progenitor cells; TrPC, trunk progenitor cells; WT, wild type; qRT-PCR, quantitative real-time polymerase chain reaction; rER, rough endoplasmic reticulum.

Abstract

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