Islet Pericytes Are Required for β-Cell Maturity

Mohr–Sasson, Aya; Rachi, Eleonor; Sakhneny, Lina; Baer, Daria; Lisnyansky, Michal; Epshtein, Alona; Landsman, Limor

doi:10.2337/db16-0365

Cited by 61 publications

(76 citation statements)

References 25 publications

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“…In particular, impaired GSIS in isolated islets ex vivo from tamoxifen-injected Myh11-CreER T2 ;NGF f/f mice highlights an essential role for NGF produced by intra-islet pericytes in β-cell function. Recently, diphtheria toxin-mediated killing of islet pericytes was found to impair GSIS in mice (Sasson et al, 2016), supporting the significance of these cell types within the islet micro-environment. Although β-cells express NGF, we show that loss of β-cell-derived NGF does not compromise glucose homeostasis in vivo .…”

Section: Discussionmentioning

confidence: 88%

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

et al. 2016

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Summary Insulin secretion by pancreatic islet β-cells is critical for glucose homeostasis, and a blunted β-cell secretory response is an early deficit in type 2 diabetes. Here, we uncover a regulatory mechanism by which glucose recruits vascular-derived neurotrophins to control insulin secretion. Nerve Growth Factor (NGF), a classical trophic factor for nerve cells, is expressed in pancreatic vasculature while its TrkA receptor is localized to islet β-cells. High glucose rapidly enhances NGF secretion, and increases TrkA phosphorylation in mouse and human islets. Tissue-specific deletion of NGF, TrkA, or acute disruption of TrkA signaling impairs glucose tolerance and insulin secretion in mice. We show that internalized TrkA receptors promote insulin granule exocytosis via F-actin reorganization. Furthermore, NGF treatment augments glucose-induced insulin secretion in human islets. These findings reveal a non-neuronal role for neurotrophins, and identify a new regulatory pathway in insulin secretion that can be targeted to ameliorate β-cell dysfunction.

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Section: Discussionmentioning

confidence: 88%

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

et al. 2016

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“…Although endothelial cells are not targeted by the Nkx3.2 -Cre mouse line1140, they might be affected by changes in the pancreatic mesenchyme. We therefore stained pancreatic tissues of Nkx3.2 -Cre; Ptch1 flox/flox and non-transgenic e18.5 embryos for the endothelial marker Platelet Endothelial Cell Adhesion Molecule 1 (PECAM1).…”

Section: Resultsmentioning

confidence: 99%

“…Of note, β-cell development was shown by others to be more affected than α-cells from deregulated pancreatic Hh25, further suggesting their specific growth rate is dependent on restrained Hh signaling. While β-cell function was shown to require cells in the islet microenvironment3840, the postnatal lethality of Nkx3.2 -Cre; Ptch1 flox/flox mice prevents us from being able to directly study the role of mesenchymal Hh signaling in this process. Nevertheless, the abnormal endocrine composition observed in transgenic mice would have likely affected the levels of secreted hormones.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Mesenchyme Regulates Islet Cellular Composition in a Patched/Hedgehog-Dependent Manner

Hibsher

Epshtein

Oren

et al. 2016

Sci Rep

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Pancreas development requires restrained Hedgehog (Hh) signaling activation. While deregulated Hh signaling in the pancreatic mesenchyme has been long suggested to be detrimental for proper organogenesis, this association was not directly shown. Here, we analyzed the contribution of mesenchymal Hh signaling to pancreas development. To increase Hh signaling in the pancreatic mesenchyme of mouse embryos, we deleted Patched1 (Ptch1) in these cells. Our findings indicate that deregulated Hh signaling in mesenchymal cells was sufficient to impair pancreas development, affecting both endocrine and exocrine cells. Notably, transgenic embryos displayed disrupted islet cellular composition and morphology, with a reduced β-cell portion. Our results indicate that the cell-specific growth rates of α- and β-cell populations, found during normal development, require regulated mesenchymal Hh signaling. In addition, we detected hyperplasia of mesenchymal cells upon elevated Hh signaling, accompanied by them acquiring smooth-muscle like phenotype. By specifically manipulating mesenchymal cells, our findings provide direct evidence for the non-autonomous roles of the Hh pathway in pancreatic epithelium development. To conclude, we directly show that regulated mesenchymal Hh signaling is required for pancreas organogenesis and establishment of its proper cellular composition.

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“…In the adult, beta-cell function and mass were shown to depend on cells in their microenvironment, including neuronal, immune, and endothelial cells, as well as pericytes111213. During injury, endothelial cells were shown to recruit immune cells to the pancreas to promote beta-cell replication13.…”

Section: Introductionmentioning

confidence: 99%

“…Endothelial cells were further shown to produce extracellular matrix (ECM) components to support insulin expression and beta-cell function14. We recently demonstrated the requirement of islet pericytes for beta-cell function11. Lastly, cells of the pancreatic stroma were shown to regulate the progression of pancreatic ductal adenocarcinoma (PDAC)1516.…”

Section: Introductionmentioning

confidence: 99%

Isolating and Analyzing Cells of the Pancreas Mesenchyme by Flow Cytometry

Epshtein

Sakhneny

Landsman

2017

JoVE

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The pancreas is comprised of epithelial cells that are required for food digestion and blood glucose regulation. Cells of the pancreas microenvironment, including endothelial, neuronal, and mesenchymal cells were shown to regulate cell differentiation and proliferation in the embryonic pancreas. In the adult, the function and mass of insulin-producing cells were shown to depend on cells in their microenvironment, including pericyte, immune, endothelial, and neuronal cells. Lastly, changes in the pancreas microenvironment were shown to regulate pancreas tumorigenesis. However, the cues underlying these processes are not fully defined. Therefore, characterizing the different cell types that comprise the pancreas microenvironment and profiling their gene expression are crucial to delineate the tissue development and function under normal and diseased states. Here, we describe a method that allows for the isolation of mesenchymal cells from the pancreas of embryonic, neonatal, and adult mice. This method utilizes the enzymatic digestion of mouse pancreatic tissue and the subsequent fluorescence-activated cell sorting (FACS) or flow-cytometric analysis of labeled cells. Cells can be labeled by either immunostaining for surface markers or by the expression of fluorescent proteins. Cell isolation can facilitate the characterization of genes and proteins expressed in cells of the pancreas mesenchyme. This protocol was successful in isolating and culturing highly enriched mesenchymal cell populations from the embryonic, neonatal, and adult mouse pancreas.

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Islet Pericytes Are Required for β-Cell Maturity

Cited by 61 publications

References 25 publications

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

Pancreatic Mesenchyme Regulates Islet Cellular Composition in a Patched/Hedgehog-Dependent Manner

Isolating and Analyzing Cells of the Pancreas Mesenchyme by Flow Cytometry

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