Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway

Sakikubo, Morito; Furuyama, Kenichiro; Horiguchi, Michiko; Hosokawa, Shinichi; Aoyama, Yoshiki; Tsuboi, Kunihiko; Goto, Toshihiko; Hirata, Koji; Masui, Toshihiko; Dor, Yuval; Fujiyama, Tomoyuki; Hoshino, Mikio; Üemoto, Shinji; Kawaguchi, Yoshiya

doi:10.1038/s41598-018-34093-4

Cited by 22 publications

(20 citation statements)

References 34 publications

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“…Instead, Pdx1-inactivated b cells lose their b cell identity either by losing pancreatic hormone expression or transdifferentiation to glucagon-expressing cells [32]. On the other hand, we previously reported that Ptf1a inactivation in adult acinar cells causes rapid and severe apoptosis via ER stress and a reduction in organ size, mostly due to cell apoptosis but also in exceptional cases transdifferentiation to duct cell type [14]. In the present study, we found that Pdx1-depleted acinar cells do not show apparent apoptosis or transdifferentiation to other cell types, but instead become senescent.…”

Section: Discussionmentioning

confidence: 97%

“…All tissue preparation was performed with cardiac perfusion fixation as previously described . Briefly, after anesthetizing the mice, we infused wash solution (0.1 m phosphate buffer containing 5 m m EGTA, 2 m m MgCl 2 and 0.9% NaCl) into the left ventricle for 1 min to wash out blood and then infused fixation solution (0.1 m phosphate buffer containing 2 m m MgCl 2, 5 m m EGTA, 4% paraformaldehyde, 2% glutaraldehyde and 30% sucrose) for 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…For X‐Gal staining, frozen sections were cut into 4‐μm‐thick slices and reacted as previously reported . The sections were incubated for 30 min at room temperature with Protein Block (Dako, Glostrup, Denmark), followed by overnight incubation at 4 °C with primary antibodies.…”

Section: Methodsmentioning

confidence: 99%

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Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice

et al. 2019

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In this study, we used tamoxifen‐inducible Elastase‐Cre–mediated inactivation of pancreatic and duodenal homeobox1 (Pdx1), an indispensable gene during embryonic pancreatogenesis, to investigate the role of Pdx1 in adult pancreatic exocrine tissue. We found that Pdx1 depletion in approximately 50% of acinar cell mass did not show any macroscopic phenotype. Lineage tracing experiments revealed that the percentage of Pdx1‐depleted cells did not change initially but gradually decreased, while the proliferation of Pdx1‐preserved cells increased. Electron microscopic analysis showed the emergence of round‐shaped mitochondria with less cristae, dilated ER lumen and increased number of autophagosomes but no apoptosis. Instead, Pdx1‐depleted acinar cells became senescent. These findings indicate that intracellular stress caused by Pdx1 inactivation triggers the senescence‐associated secretory phenotype to maintain organ homeostasis in this model.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

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Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice

et al. 2019

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“…Immune cell infiltration, along with chemokine and cytokine cascade-mediated inflammation, plays a critical role in the development of this disease[ 15 , 16 ]. Although increasing evidence shows that inhibiting the immune cells (neutrophils) or specific adhesion molecules (P-selectin, lymphocyte function antigen-1, and CD11a/CD18) may have a therapeutic effect on excessive inflammatory responses in AP[ 17 - 20 ], no drug that effectively modulates the outcome of AP has been identified[ 21 ]. It is urgent to find a novel therapeutic target for the treatment of AP.…”

Section: Discussionmentioning

confidence: 99%

P-selectin glycoprotein ligand 1 deficiency prevents development of acute pancreatitis by attenuating leukocyte infiltration

Zhang

Zhu

Jiang

et al. 2020

WJG

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BACKGROUND Acute pancreatitis (AP) is rapid-onset pancreatic inflammation that causes local and systemic inflammatory response syndrome (SIRS) with high morbidity and mortality, but no approved therapies are currently available. P-selectin glycoprotein ligand 1 (PSGL-1) is a transmembrane glycoprotein to initiate inflammatory responses. We hypothesized that PSGL-1 may be involved in the development of AP and would be a new target for the treatment of AP. AIM To investigate the role and mechanism of PSGL-1 in the development of AP. METHODS The PSGL-1 expression on leukocytes was detected in peripheral blood of AP patients and volunteers. Pancreatic injury, inflammatory cytokines expression, and inflammatory cell infiltration was measured in AP mouse models induced with PSGL-1 knockout ( PSGL-1 -/- ) and wild-type ( PSGL-1 +/+ ) mice. Leukocyte-endothelial cell adhesion was measured in a peripheral blood mononuclear cell (PBMC)-endothelial cell coculture system. RESULTS The expression of PSGL-1 on monocytes and neutrophils was significantly increased in AP patients. Compared with PSGL-1 +/+ mice, PSGL-1 -/- AP mice induced by caerulein exhibited lower serum amylase, less Interleukin-1beta (IL-1beta) and Interleukin-6 (IL-6) expression, less neutrophil and macrophage infiltration, and reduced peripheral neutrophil and monocyte accounts. PSGL-1 deficiency alleviated leukocyte-endothelial cell adhesion via IL-6 but not IL-1beta. CONCLUSION PSGL-1 deficiency effectively inhibits the development of AP by preventing leukocyte-endothelial cell adhesion via IL-6 stimulation and may become a potential therapeutic target for treating AP.

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“…In addition, Ptf1a dosage experiments from the homozygous-to-null status done using conditional Ptf1a KO mice, showed pancreatic hypoplasia and glucose intolerance in a dosage-dependent manner (Fukuda et al, 2008). In addition, it was shown that Ptf1a null acinar cells have enhanced ER stress and accelerated apoptosis evidenced by increased PERK, eIF2, ATF4 and ATF6 pathways, suppression of the IRE1 pathways and increased CHOP levels, leading to reduced pancreatic size (Sakikubo et al, 2018). The authors proposed that the shift in cellular identity (acinar to ductal-like) may be a compensatory response to promote cell survival.…”

Section: Molecular Phenotypementioning

confidence: 99%

Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes

Caballero

Gorgogietas

Arroyo

et al. 2021

International Review of Cell and Molecular Biology

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Monogenetic forms of diabetes represent 1% to 5% of all diabetes cases and are caused by mutations in a single gene. These mutations, affecting genes involved in pancreatic β-cell development, function and survival or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The abundance of each monogenic form of the disease and the severity of their symptoms depend on the nature of the mutation, the function of the affected gene and, in some cases, the influence of additional genetic or environmental factors that modulate severity and penetrance. In some patients, diabetes is accompanied by other syndromic features such as deafness, blindness, microcephaly, liver and intestinal defects, between others. The age of diabetes onset may also vary from neonatal presentations until early adulthood manifestations. Since the different mutations result in diverse clinical presentations, patients usually need different treatments that range from just diet and exercise, to the requirement of exogenous insulin or other hypoglycaemic drugs e.g. sulfonylureas or glucagon like peptide 1 analogs to control their normoglycemia. As a consequence, awareness and correct diagnosis are crucial for the proper management and treatment of monogenic diabetes patients. In this chapter, we describe mutations causing different monogenic forms of diabetes associated with inadequate pancreas development or impaired β-cell function and survival, and discuss the molecular mechanisms involved in β-cell demise.

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Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway

Cited by 22 publications

References 34 publications

Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice

Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice

P-selectin glycoprotein ligand 1 deficiency prevents development of acute pancreatitis by attenuating leukocyte infiltration

Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes

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