scholarly journals Placental growth factor in beta cells plays an essential role in gestational beta-cell growth

2020 ◽  
Vol 8 (1) ◽  
pp. e000921
Author(s):  
Weixia Yang ◽  
Yinan Jiang ◽  
Yan Wang ◽  
Ting Zhang ◽  
Qun Liu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Placental Growth Factor ◽  
Beta Cell Proliferation ◽  
Insulin Promoter ◽  
Beta Cell Growth

ObjectivePancreatic beta cells proliferate in response to metabolic requirements during pregnancy, while failure of this response may cause gestational diabetes. A member of the vascular endothelial growth factor family, placental growth factor (PlGF), typically plays a role in metabolic disorder and pathological circumstance. The expression and function of PlGF in the endocrine pancreas have not been reported and are addressed in the current study.Research design and methodsPlGF levels in beta cells were determined by immunostaining or ELISA in purified beta cells in non-pregnant and pregnant adult mice. An adeno-associated virus (AAV) serotype 8 carrying a shRNA for PlGF under the control of a rat insulin promoter (AAV–rat insulin promoter (RIP)–short hairpin small interfering RNA for PlGF (shPlGF)) was prepared and infused into mouse pancreas through the pancreatic duct to specifically knock down PlGF in beta cells, and its effects on beta-cell growth were determined by beta-cell proliferation, beta-cell mass and insulin release. A macrophage-depleting reagent, clodronate, was coapplied into AAV-treated mice to study crosstalk between beta cells and macrophages.ResultsPlGF is exclusively produced by beta cells in the adult mouse pancreas. Moreover, PlGF expression in beta cells was significantly increased during pregnancy. Intraductal infusion of AAV–RIP–shPlGF specifically knocked down PlGF in beta cells, resulting in compromised beta-cell proliferation, reduced growth in beta-cell mass and impaired glucose tolerance during pregnancy. Mechanistically, PlGF depletion in beta cells reduced islet infiltration of trophic macrophages, which appeared to be essential for gestational beta-cell growth.ConclusionsOur study suggests that increased expression of PlGF in beta cells may trigger gestational beta-cell growth through recruited macrophages.

scholarly journals Pronounced proliferation of non-beta cells in response to beta-cell mitogens in isolated human islets of Langerhans

2020 ◽  
Author(s):  
Hasna Maachi ◽  
Julien Ghislain ◽  
Caroline Tremblay ◽  
Vincent Poitout
Keyword(s):  
Flow Cytometry ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Beta Cell ◽  
Beta Cells ◽  
Single Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Cytokeratin 19 ◽  
Beta Cell Proliferation

ABSTRACTThe potential to treat diabetes by increasing beta-cell mass is driving a major effort to identify beta-cell mitogens. Demonstration of mitogen activity in human beta cells is frequently performed in ex vivo assays. However, disparities in the efficacy of beta-cell mitogens between studies led us to investigate the sources of this variability. We obtained 27 male (16) and female (11) human islet batches from multiple centers covering a range of donor ages (18-65 years) and BMI (16.4-38.5). Islets were kept intact or dispersed into single cells and cultured in the presence of the beta-cell mitogens harmine, glucose, and heparin-binding epidermal growth factor-like growth factor (HB-EGF), and subsequently analyzed for cell proliferation by immunochemistry or flow cytometry. Harmine and HB-EGF promoted human beta-cell proliferation, whereas the effect of glucose was assay-dependent. In addition, harmine potently stimulated alpha-cell proliferation and both harmine and HB-EGF increased proliferation of insulin- and glucagon-negative cells, including cytokeratin 19-positive cells. These results suggest that assessment of beta-cell mitogens requires complementary approaches and rigorous identification of cell identity. This is better achieved by flow cytometry that eliminates the subjectivity of visual scoring and enables simultaneous assessment of several endocrine and proliferation markers in higher numbers of cells.

scholarly journals Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Rebeca Fernandez-Ruiz ◽  
Ainhoa García-Alamán ◽  
Yaiza Esteban ◽  
Joan Mir-Coll ◽  
Berta Serra-Navarro ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Proliferation ◽  
Cell Replication ◽  
Trophic Effect ◽  
Beta Cell Replication

AbstractExpanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice. We show that Wisp1 promotes endogenous and transplanted adult beta cell proliferation in vivo. We validate these findings using isolated mouse and human islets and find that the beta cell trophic effect of Wisp1 is dependent on Akt signaling. In summary, our study reveals the role of Wisp1 as an inducer of beta cell replication, supporting the idea that the use of young blood factors may be a useful strategy to expand adult beta cell mass.

scholarly journals Postnatal activation of hypoxia pathway disrupts β-cell functional maturation

2021 ◽  
Author(s):  
Juxiang Yang ◽  
Batoul Hammoud ◽  
Abigail Ridler ◽  
Amanda M Ackermann ◽  
Kyoung-Jae Won ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Proliferation ◽  
Rat Pups ◽  
Functional Maturation ◽  
The Impact ◽  
Glucose Threshold

Objective: Hypoxic injuries occurring during the perinatal period can lead to persistent hyperinsulinism and profound hypoglycemia in newborns. We studied the impact of hypoxia-inducible pathway on the postnatal beta-cell function. Methods: Rat pups were treated daily between postnatal day (P)7 to P10 with adaptaquin (AQ), an inhibitor of prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor 1A (HIF1A). In parallel, mouse pups were placed in a hypoxic chamber between embryonic day (E)19 to P6. Dynamic insulin secretion was assessed in both models by islet perifusions. Changes in gene expression were assessed by whole-islet RNA sequencing. Results: AQ-treated rat pups and hypoxic mouse pups were hypoglycemic and had higher levels of serum insulin. The AQ-/hypoxia-treated islets showed a decreased glucose threshold for insulin secretion compared to controls, indicative of a delay in beta-cell postnatal functional maturation. Islet morphometric analysis in the AQ-treated pups showed an increase in insulin area per pancreas, but no change in the number of islets or in the number of beta-cells per islet, consistent with a higher average size of beta-cells. Differential transcriptomic analysis showed upregulation of the expected HIF1A target genes. AQ-treated rat pups had decreased expression of cell cycle genes and decreased numbers of proliferating beta;-cells. Conclusion: We showed that hypoxia and pharmacologic activation of the hypoxia inducible pathway in early postnatal period leads to hyperinsulinism, due to the persistence of a low glucose threshold for insulin secretion. This exaggerated activation of hypoxia pathway also decreased early postnatal beta-cell proliferation, suggesting it can impact adult beta-cell mass and diabetes risk.

scholarly journals The Harmine and Exendin-4 Combination Markedly Expands Human Beta Cell Mass In Vivo: Quantification and Visualization By iDISCO+ 3D Imaging

2020 ◽  
Author(s):  
Carolina Rosselot ◽  
Alexandra Alvarsson ◽  
Peng Wang ◽  
Yansui Li ◽  
Kunal Kumar ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Proliferation ◽  
Light Sheet Microscopy ◽  
Human Beta Cell

AbstractSince all diabetes results from reductions in numbers of functional pancreatic beta cells, beta cell regenerative drugs are required for optimal and scalable future diabetes treatment. While many diabetes drugs are in clinical use, none increases human beta cell numbers. We have shown that a combination of the DYRK1A inhibitor, harmine, with the GLP1 receptor agonist, exendin-4, markedly increases human beta cell proliferation in vitro. However, technological limitations have prevented assessment of human beta cell mass in vivo. Here, we describe a novel method that combines iDISCO+ tissue clearing, insulin immunolabeling, light sheet microscopy, and volumetric quantification of human beta cells transplanted into immunodeficient mice. We demonstrate a striking seven-fold in vivo increase in human beta cell mass in response to three months of combined harmine-exendin-4 combination infusion, accompanied by lower blood glucose levels, increased plasma human insulin concentrations and enhanced beta cell proliferation. These studies unequivocally demonstrate for the first time that pharmacologic human beta cell expansion is a realistic and achievable path to diabetes therapy, and provide a rigorous, entirely novel and reproducible tool for quantifying human beta cell mass in vivo.

scholarly journals Pre-Eclampsia-Associated Reduction in Placental Growth Factor Impaired Beta Cell Proliferation Through PI3k Signalling

2015 ◽  
Vol 36 (1) ◽  
pp. 34-43 ◽  
Author(s):  
Jun Li ◽  
Huanchun Ying ◽  
Guiyang Cai ◽  
Quan Guo ◽  
Lizhu Chen
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Number ◽  
Placental Growth Factor ◽  
Conditioned Media ◽  
Beta Cell Proliferation

Background/Aim: Reduction in serum placental growth factor (PLGF) frequently co-occurs with preeclampsia (PE) and gestational diabetes mellitus (GDM). Recently, we reported that impairment in gestational beta-cell mass growth may result from PE-associated reduction in PLGF and lead to development of GDM. Here, we studied the underlying mechanisms. Methods: We co-cultured primary mouse beta cells with mouse islet endothelial cells (MS1), with or without PLGF. We also cultured beta cells in conditioned media from PLGF-treated MS1. Specific signal-pathway inhibitors were applied to cultured beta cells in conditioned media from PLGF-treated MS1. We analysed beta-cell proliferation by BrdU incorporation. We analysed changes in cell number by a MTT assay. We analysed protein levels of cell-cycle regulators in beta cells by Western blot. Results: PLGF itself failed to induce beta-cell proliferation, but significantly augmented proliferation of beta cells co-cultured with MS1, which resulted in significant increases in cell number. Conditioned media from the PLGF-treated MS1 cells similarly induced beta-cell proliferation, which was abolished by inhibition of PI3k/Akt signalling, but not by inhibition of either ERK/MAPK or JNK signalling. The induction of beta-cell proliferation by PLGF-treated MS1 cells appeared to involve decreases in cell-cycle inhibitors p21 and p27, and increases in cell-cycle activators CDK4 and CyclinD1. Conclusion: Gestational PLGF may target islet endothelial cells to release growth factors that activate PI3k/Akt signalling in beta cells to increase their proliferation. PE-associated reduction in PLGF impairs these processes to result in GDM.

scholarly journals Islet Regeneration: Endogenous and Exogenous Approaches

2021 ◽  
Vol 22 (7) ◽  
pp. 3306
Author(s):  
Fiona M. Docherty ◽  
Lori Sussel
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Cell Mass ◽  
Cell Formation ◽  
Beta Cell Mass ◽  
Beta Cell Proliferation ◽  
Significant Research ◽  
Cell Sources

Both type 1 and type 2 diabetes are characterized by a progressive loss of beta cell mass that contributes to impaired glucose homeostasis. Although an optimal treatment option would be to simply replace the lost cells, it is now well established that unlike many other organs, the adult pancreas has limited regenerative potential. For this reason, significant research efforts are focusing on methods to induce beta cell proliferation (replication of existing beta cells), promote beta cell formation from alternative endogenous cell sources (neogenesis), and/or generate beta cells from pluripotent stem cells. In this article, we will review (i) endogenous mechanisms of beta cell regeneration during steady state, stress and disease; (ii) efforts to stimulate endogenous regeneration and transdifferentiation; and (iii) exogenous methods of beta cell generation and transplantation.

scholarly journals Multi-Organ Crosstalk with Endocrine Pancreas: A Focus on How Gut Microbiota Shapes Pancreatic Beta-Cells

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 104
Author(s):  
Elisa Fernández-Millán ◽  
Carlos Guillén
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Cell Biology ◽  
Pancreatic Beta Cells ◽  
Metabolic Diseases ◽  
Cell Function ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Short Chain Fatty Acids

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells communicate with metabolic and non-metabolic tissues provides a novel area for investigation and implicates the importance of inter-organ communication in the pathology of metabolic diseases such as T2D. In this review, we provide an overview of secreted factors from diverse organs and tissues that have been shown to impact beta-cell biology. Specifically, we discuss experimental and clinical evidence in support for a role of gut to beta-cell crosstalk, paying particular attention to bacteria-derived factors including short-chain fatty acids, lipopolysaccharide, and factors contained within extracellular vesicles that influence the function and/or the survival of beta cells under normal or diabetogenic conditions.

scholarly journals Update on the Protective Molecular Pathways Improving Pancreatic Beta-Cell Dysfunction

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
François Mach ◽  
Franco Dallegri ◽  
Giorgio Luciano Viviani ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Molecular Pathways ◽  
Cell Dysfunction

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.

scholarly journals Dynamic Regulation of JAK-STAT Signaling Through the Prolactin Receptor Predicted by Computational Modeling

2020 ◽  
Author(s):  
Ryland D. Mortlock ◽  
Senta K. Georgia ◽  
Stacey D. Finley
Keyword(s):  
Experimental Data ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Prolactin Receptor ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Receptor Internalization ◽  
Proliferative Potential ◽  
Stat Signaling

Abstract Introduction The expansion of insulin-producing beta cells during pregnancy is critical to maintain glucose homeostasis in the face of increasing insulin resistance. Prolactin receptor (PRLR) signaling is one of the primary mediators of beta cell expansion during pregnancy, and loss of PRLR signaling results in reduced beta cell mass and gestational diabetes. Harnessing the proliferative potential of prolactin signaling to expand beta cell mass outside of the context of pregnancy requires quantitative understanding of the signaling at the molecular level. Methods A mechanistic computational model was constructed to describe prolactin-mediated JAK-STAT signaling in pancreatic beta cells. The effect of different regulatory modules was explored through ensemble modeling. A Bayesian approach for likelihood estimation was used to fit the model to experimental data from the literature. Results Including receptor upregulation, with either inhibition by SOCS proteins, receptor internalization, or both, allowed the model to match experimental results for INS-1 cells treated with prolactin. The model predicts that faster dimerization and nuclear import rates of STAT5B compared to STAT5A can explain the higher STAT5B nuclear translocation. The model was used to predict the dose response of STAT5B translocation in rat primary beta cells treated with prolactin and reveal possible strategies to modulate STAT5 signaling. Conclusions JAK-STAT signaling must be tightly controlled to obtain the biphasic response in STAT5 activation seen experimentally. Receptor up-regulation, combined with SOCS inhibition, receptor internalization, or both is required to match experimental data. Modulating reactions upstream in the signaling can enhance STAT5 activation to increase beta cell survival.

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