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Generation of Scaffold-free, Three-dimensional Insulin Expressing Pancreatoids from Mouse Pancreatic Progenitors In Vitro
Published on: June 2, 2018
Angiotensin II type 2 receptor regulates the development of pancreatic endocrine cells in mouse embryos
Kwan Keung Leung1, Juan Liang, Shuiling Zhao
1School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Background:
We previously identified a local renin-angiotensin system (RAS) regulating the differentiation of an isolated population of human pancreatic progenitor cells. Major RAS components that regulate organogenesis have been also described in embryos; however, it is not known whether a local RAS is present in the fetal pancreas. We now hypothesize that angiotensin II type 1 (AT1 ) and type 2 (AT2 ) receptors are expressed in mouse embryonic pancreas and involved in regulating endocrine cell development.
Results:
Differential expression of AT1 and AT2 receptors was observed in the mouse pancreata in late embryogenesis. Systemic AT2 , but not AT1 , receptor blockade during the second transition in pancreatic development (from embryonic day 12.0 onward) reduced the β-cell to α-cell ratio of the neonate islets, impaired their insulin secretory function and the glucose tolerance of the pups. Studies with pancreas explants ex vivo revealed regulation by AT2 receptors of the differentiation of pancreatic progenitors into insulin-producing cells and of the proliferation of the differentiated cell, actions that did not result from reduced angiogenesis as a secondary effect of AT2 receptor antagonism.
Conclusions:
These data revealed an AT2 receptor-mediated mechanism regulating pancreatic endocrine cell development in vivo.
Insights
The study found that the angiotensin II type 2 (AT2) receptor regulates pancreatic endocrine cell development. Blocking AT2 receptors impaired insulin production and glucose tolerance in developing mice.
Area of Science:
- Endocrinology
- Developmental Biology
- Molecular Biology
Background:
- A local renin-angiotensin system (RAS) regulates human pancreatic progenitor cell differentiation.
- RAS components are known to regulate organogenesis in embryos.
- The presence and role of a local RAS in the fetal pancreas remain unclear.
Purpose of the Study:
- To investigate the expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the embryonic mouse pancreas.
- To determine the role of AT1 and AT2 receptors in regulating pancreatic endocrine cell development.
Main Methods:
- Examined differential expression of AT1 and AT2 receptors in embryonic mouse pancreata.
- Utilized systemic receptor blockade of AT2 (and AT1) during a critical window of pancreatic development.
- Conducted ex vivo studies using pancreas explants to assess receptor function.
Main Results:
- AT1 and AT2 receptors showed differential expression in late embryogenesis.
- AT2 receptor blockade reduced the beta-cell to alpha-cell ratio, impaired insulin secretion, and worsened glucose tolerance.
- Ex vivo studies confirmed AT2 receptor regulation of progenitor differentiation and cell proliferation, independent of angiogenesis.
Conclusions:
- An AT2 receptor-mediated mechanism regulates pancreatic endocrine cell development in vivo.
- These findings highlight the specific role of the AT2 receptor in fetal pancreas development.
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