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?-Cells are not generated in pancreatic duct ligation-induced injury in adult mice.

ABSTRACT: The existence of adult ?-cell progenitors remains the most controversial developmental biology topic in diabetes research. It has been reported that ?-cell progenitors can be activated by ductal ligation-induced injury of adult mouse pancreas and apparently act in a cell-autonomous manner to double the functional ?-cell mass within a week by differentiation and proliferation. Here, we demonstrate that pancreatic duct ligation (PDL) does not activate progenitors to contribute to ?-cell mass expansion. Rather, PDL stimulates massive pancreatic injury, which alters pancreatic composition and thus complicates accurate measurement of ?-cell content via traditional morphometry methodologies that superficially sample the pancreas. To overcome this potential bias, we quantified ?-cells from the entire pancreas and observed that ?-cell mass and insulin content are totally unchanged by PDL-induced injury. Lineage-tracing studies using sequential administration of thymidine analogs, rat insulin 2 promoter-driven cre-lox, and low-frequency ubiquitous cre-lox reveal that PDL does not convert progenitors to the ?-cell lineage. Thus, we conclude that ?-cells are not generated in injured adult mouse pancreas.

SUBMITTER: Rankin MM

PROVIDER: S-EPMC3636617 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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β-Cells are not generated in pancreatic duct ligation-induced injury in adult mice.

Rankin Matthew M MM Wilbur Christopher J CJ Rak Kimberly K Shields Emily J EJ Granger Anne A Kushner Jake A JA

Diabetes 20130124 5

The existence of adult β-cell progenitors remains the most controversial developmental biology topic in diabetes research. It has been reported that β-cell progenitors can be activated by ductal ligation-induced injury of adult mouse pancreas and apparently act in a cell-autonomous manner to double the functional β-cell mass within a week by differentiation and proliferation. Here, we demonstrate that pancreatic duct ligation (PDL) does not activate progenitors to contribute to β-cell mass expan ...[more]

PMID: 23349489

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Project description:Liver dysfunction and cirrhosis affect vasculature in several organ systems and cause impairment of organ functions, thereby increasing morbidity and mortality. If a mouse model of hepatopulmonary syndrome (HPS) could be established, greater insight into the genetic basis of the disease would be gained. Our objectives were to establish a mouse model of lung injury after common bile duct ligation (CBDL) and to investigate pulmonary pathogenesis for application in future therapeutic approaches. Balb/c mice were subjected to CBDL. Immunohistochemical analyses and real-time quantitative reverse transcriptional polymerase chain reaction were performed on pulmonary tissues. The presence of HPS markers were detected by western blot and microarray analyses. We observed extensive proliferation of CD31-positive pulmonary vascular endothelial cells 2 weeks after CBDL, and identified 11 up-regulated and 8 down-regulated proteins that were associated with angiogenesis. MMP-9 protein was highly expressed at 3 weeks after CBDL, and less expressed in lungs of the control group. Contrary to our expectation, lung pathology in our mouse model exhibited differences from that of rat models, and the mechanisms responsible for these differences are unknown. This phenomenon may be explained by contrasting processes related to TNF induction of angiogenic signaling pathways in the inflammatory phase; thus, we suggest that our mouse model can be applied to pulmonary pathological analyses in the inflammatory phase, i.e., to systemic inflammatory response syndrome, acute lung injury, and MOD syndrome. After induction of anesthesia, a median abdominal incision was made and the common bile duct was identified. The duct was dissected carefully under a microscope, and doubly ligated with 7-0 Prolene and transected. In the sham operation (control) group, the duct was dissected without common bile duct ligation. Mice were sacrificed at 2 and 3 weeks after surgery. CD31-positive cells were assembled from three mice in each group.

Project description:Impaired intestinal barrier function promotes the progression of various liver diseases, including cholestatic liver diseases. The close association of primary sclerosing cholangitis (PSC) with inflammatory bowel disease highlights the importance of the gut-liver axis. It has been reported that bile duct ligation (BDL)-induced liver fibrosis is significantly reduced in C/EBP homologous protein knockout (CHOP-/- ) mice. However, the underlying mechanisms remain unclear. In the current study, we demonstrate that BDL induces striking and acute hepatic endoplasmic reticulum (ER) stress responses after 1 day, which return to normal after 3 days. No significant hepatocyte apoptosis is detected 7-14 days following BDL. However, the inflammatory response is significantly increased after 7 days, which is similar to what we found in human PSC liver samples. BDL-induced loss of stemness in intestinal stem cells (ISCs), disruption of intestinal barrier function, bacterial translocation, activation of hepatic inflammation, M2 macrophage polarization and liver fibrosis are significantly reduced in CHOP-/- mice. In addition, intestinal organoids derived from CHOP-/- mice contain more and longer crypt structures than those from wild-type (WT) mice, which is consistent with the upregulation of stem cell markers (leucine-rich repeat-containing G-protein-coupled receptor 5, olfactomedin 4, and SRY [sex determining region Y]-box 9) and in vivo findings that CHOP-/- mice have longer villi and crypts as compared to WT mice. Similarly, mRNA levels of CD14, interleukin-1β, tumor necrosis factor-alpha, and monocyte chemotactic protein-1 are increased and stem cell proliferation is suppressed in the duodenum of patients with cirrhosis.ConclusionActivation of ER stress and subsequent loss of stemness of ISCs plays a critical role in BDL-induced systemic inflammation and cholestatic liver injury. Modulation of the ER stress response represents a potential therapeutic strategy for cholestatic liver diseases as well as other inflammatory diseases. (Hepatology 2018;67:1441-1457).

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?-Cells are not generated in pancreatic duct ligation-induced injury in adult mice.

Publications

β-Cells are not generated in pancreatic duct ligation-induced injury in adult mice.

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