Bmi1 Is Required for Regeneration of the Exocrine Pancreas in Mice

Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California 94143-0573, USA.
Gastroenterology (Impact Factor: 16.72). 05/2012; 143(3):821-31.e1-2. DOI: 10.1053/j.gastro.2012.05.009
Source: PubMed


Bmi1 is a member of the Polycomb protein family and represses transcription by modifying chromatin organization at specific promoters. Bmi1 is implicated in the control of stem cell self-renewal and has been shown to regulate cell proliferation, tissue homeostasis, and differentiation. Bmi1 is present in a subpopulation of self-renewing pancreatic acinar cells and is expressed in response to pancreatic damage. We investigated the role of Bmi1 in regeneration of exocrine pancreas.
Acute pancreatitis was induced in Bmi1(-/-) mice with cerulein; pancreatic cell regeneration, differentiation, and apoptosis were assessed. Cultured Bmi1(-/-) and wild-type primary acini were analyzed in vitro to determine acinar-specific consequences of Bmi1 deletion. To investigate cell autonomous versus non-cell autonomous roles for Bmi1 in vivo, pancreatitis was induced in Bmi1(-/-) mice reconstituted with a wild-type hematopoietic system.
Bmi1 expression was up-regulated in the exocrine pancreas during regeneration after cerulein-induced pancreatitis. Exocrine regeneration was impaired following administration of cerulein to Bmi1(-/-) mice. Pancreata of Bmi1(-/-) mice were hypoplastic, and the exocrine pancreas was replaced with ductal metaplasia that had increased apoptosis and decreased cell proliferation compared with that of wild-type mice. Expression of Cdkn2a and p53-dependent apoptotic genes was markedly up-regulated in Bmi1(-/-) pancreas compared with wild-type mice after injury. Furthermore, after transplantation of bone marrow from wild-type to Bmi1(-/-) mice, the chimeric mice had intermediate levels of pancreatic hypoplasia and significant but incomplete rescue of impaired exocrine regeneration after cerulein injury.
Bmi1 contributes to regeneration of the exocrine pancreas after cerulein-induced injury through cell autonomous mechanisms, in part by regulating Cdkn2a expression, and non-cell autonomous mechanisms.

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    • "In addition to its pivotal role in PDAC initiation, acinar-to-ductal metaplasia represents a cellular adaptation process of the acinar cell in response to external stress signals which prevents stress-mediated cell death and can result in a stepwise regeneration program that reconstitutes pancreatic tissue integrity [24] [25] [26]. Either acute or chronic pancreatic inflammation results in the formation of metaplastic pancreatic lesions that can redifferentiate into acinar cells in a permissive cellular context [27]. "
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    ABSTRACT: Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC) development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation-induced signaling activation of the epidermal growth factor (EGFR) or induction of Sox9 expression, are required for tumor formation. Herein, we aimed to dissect the mechanism that links EGFR signaling to Sox9 gene expression during acinar-to-ductal metaplasia in pancreatic tissue adaptation and PDAC initiation. We show that the inflammatory transcription factor NFATc4 is highly induced and localizes in the nucleus in response to inflammation-induced EGFR signaling. Moreover, we demonstrate that NFATc4 drives acinar-to-ductal conversion and PDAC initiation through direct transcriptional induction of Sox9 . Therefore, strategies designed to disrupt NFATc4 induction might be beneficial in the prevention or therapy of PDAC.
    Full-text · Article · Jan 2016 · Stem cell International
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    • "We observed increase in expression of RING1B during endoderm differentiation, similar to our previous report (Pethe et al., 2014). BMI1 has been reported to play important role in proliferation of neural stem cells, hematopoietic stem cells, and endoderm cells by inhibition of cell cycle regulators p19/p16 (Lessard et al., 1999; Fukuda et al., 2012; Pethe et al., 2014), in the present study also; we observed increased expression of BMI1 at transcript and protein level. Xie et al. (2013) performed ChIP sequencing and showed that levels of H3K27me3 decreased during definitive endoderm formation (early differentiation) but later, total H3K27me3 levels increased as hES cells differentiated towards pancreatic lineage. "
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    ABSTRACT: Human embryonic (hES) stem cells are excellent model to study lineage specification and differentiation into various cell types. Differentiation necessitates repression of specific genes not required for a particular lineage. Polycomb Group (PcG) proteins are key histone modifiers, whose primary function is gene repression. PcG proteins form complexes called Polycomb Repressive Complexes (PRCs), which catalyze histone modifications such as H2AK119ub1, H3K27me3 and H3K9me3. PcG proteins play a crucial role during differentiation of stem cells. The expression of PcG transcripts during differentiation of hES cells into endoderm, mesoderm and ectoderm lineage is yet to be shown. In-house derived hES cell line KIND1 was differentiated into endoderm, mesoderm and ectoderm lineages; followed by characterized using RT-PCR for HNF4A, CDX2, MEF2C, TBX5, SOX1 and MAP2. qRT-PCR and western blotting was performed to compare expression of PcG transcripts and proteins across all the three lineages. We observed that cells differentiated into endoderm showed upregulation of RING1B, BMI1, EZH2 and EED transcripts. Mesoderm differentiation was characterized by significant downregulation of all PcG transcripts during later stages. BMI1 and RING1B were upregulated while EZH2, SUZ12 and EED remained low during ectoderm differentiation. Western Blotting also showed distinct expression of BMI1 and EZH2 during differentiation into three germ layers. Our study shows that hES cells differentiating into endoderm, mesoderm and ectoderm lineages show distinct PcG expression profile at transcript and protein level. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2015 · Cell Biology International
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    • "Regulation of the INK4a locus by Bmi1 and MLL1 has been implicated in the maintenance of pancreatic β cell proliferation and the capacity of β cells to recover after pancreatic islet damage [25]. Bmi1 expressing acinar and islet cells have been found in the murine pancreas and Bmi1 plays a key role in the recovery of the acinar compartment after cerulein-induced pancreatitis and diphtheria toxin-mediated acinar cell ablation in mice [26], [27]. Overexpression of Bmi1 has been noted in human pancreatic cancer samples compared to the normal pancreas [28], [29], [30]. "
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    ABSTRACT: Bmi1 is an integral component of the Polycomb Repressive Complex 1 (PRC1) and is involved in the pathogenesis of multiple cancers. It also plays a key role in the functioning of endogenous stem cells and cancer stem cells. Previous work implicated a role for cancer stem cells in the pathogenesis of pancreatic cancer. We hypothesized that Bmi1 plays an integral role in enhancing pancreatic tumorigenicity and the function of cancer stem cells in pancreatic ductal adenocarcinoma. We measured endogenous Bmi1 levels in primary human pancreatic ductal adenocarcinomas, pancreatic intraepithelial neoplasias (PanINs) and normal pancreas by immunohistochemistry and Western blotting. The function of Bmi1 in pancreatic cancer was assessed by alteration of Bmi1 expression in several cell model systems by measuring cell proliferation, cell apoptosis, in vitro invasion, chemotherapy resistance, and in vivo growth and metastasis in an orthotopic model of pancreatic cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human pancreatic cancer xenografts after Bmi1 silencing. Bmi1 was overexpressed in human PanINs, pancreatic cancers, and in several pancreatic cancer cell lines. Overexpression of Bmi1 in MiaPaCa2 cells resulted in increased proliferation, in vitro invasion, larger in vivo tumors, more metastases, and gemcitabine resistance while opposite results were seen when Bmi1 was silenced in Panc-1 cells. Bmi1 was overexpressed in the cancer stem cell compartment of primary human pancreatic cancer xenografts. Pancreatic tumorspheres also demonstrated high levels of Bmi1. Silencing of Bmi1 inhibited secondary and tertiary tumorsphere formation, decreased primary pancreatic xenograft growth, and lowered the proportion of cancer stem cells in the xenograft tissue. Our results implicate Bmi1 in the invasiveness and growth of pancreatic cancer and demonstrate its key role in the regulation of pancreatic cancer stem cells.
    Full-text · Article · Feb 2013 · PLoS ONE
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