Betacellulin-Induced α-Cell Proliferation Is Mediated by ErbB3 and ErbB4, and May Contribute to β-Cell Regeneration

Betacellulin (BTC), an epidermal growth factor family, is known to promote β-cell regeneration. Recently, pancreatic α-cells have been highlighted as a source of new β-cells. We investigated the effect of BTC on α-cells. Insulin+glucagon+ double stained bihormonal cell levels and pancreatic and duodenal homeobox-1 expression were increased in mice treated with recombinant adenovirus-expressing BTC (rAd-BTC) and β-cell-ablated islet cells treated with BTC. In the islets of rAd-BTC-treated mice, both BrdU+glucagon+ and BrdU+insulin+ cell levels were significantly increased, with BrdU+glucagon+ cells showing the greater increase. Treatment of αTC1-9 cells with BTC significantly increased proliferation and cyclin D2 expression. BTC induced phosphorylation of ErbB receptors in αTC1-9 cells. The proliferative effect of BTC was mediated by ErbB-3 or ErbB-4 receptor kinase. BTC increased phosphorylation of ERK1/2, AKT, and mTOR and PC1/3 expression and GLP-1 production in α-cells, but BTC-induced proliferation was not changed by the GLP-1 receptor antagonist, exendin-9. We suggest that BTC has a direct role in α-cell proliferation via interaction with ErbB-3 and ErbB-4 receptors, and these increased α-cells might be a source of new β-cells.

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Reversal of autoimmunity by mixed chimerism enables reactivation of β cells and transdifferentiation of α cells in diabetic NOD mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2012389117 ◽

2020 ◽

Vol 117 (49) ◽

pp. 31219-31230

Author(s):

Shanshan Tang ◽

Mingfeng Zhang ◽

Samuel Zeng ◽

Yaxun Huang ◽

Melissa Qin ◽

...

Keyword(s):

Nod Mice ◽

Lineage Tracing ◽

Mixed Chimerism ◽

Cell Regeneration ◽

Β Cells ◽

Β Cell ◽

Nonobese Diabetic ◽

Autoimmune Destruction ◽

Epidermal Growth

Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9+ductal progenitors, Nestin+mesenchymal stem cells, and glucagon-producing α cells, we have found that both reactivation of dysfunctional low-level insulin expression (insulinlo) β cells and neogenesis contribute to the regeneration, with the latter predominantly coming from transdifferentiation of α cells. These results indicate that, after reversal of autoimmunity, reactivation of β cells and transdifferentiation of α cells can provide sufficient new functional β cells to reach euglycemia in firmly established T1D.

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Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote β cell regeneration

10.1101/2020.08.28.265728 ◽

2020 ◽

Author(s):

Diane C. Saunders ◽

Kristie I. Aamodt ◽

Tiffany M. Richardson ◽

Alec Hopkirk ◽

Radhika Aramandla ◽

...

Keyword(s):

Extracellular Matrix ◽

Cell Proliferation ◽

Endothelial Cells ◽

Cell Loss ◽

Cell Regeneration ◽

Matrix Remodeling ◽

Cell Recovery ◽

Β Cells ◽

Β Cell ◽

Elevated Expression

ABSTRACTEndogenous β cell regeneration could alleviate diabetes, but proliferative stimuli within the islet microenvironment are incompletely understood. We previously found that β cell recovery following hypervascularization-induced β cell loss involves interactions with endothelial cells (ECs) and macrophages (MΦs). Here we show that proliferative ECs modulate MΦ infiltration and phenotype during β cell loss, and recruited MΦs are essential for β cell recovery. Furthermore, VEGFR2 inactivation in quiescent ECs accelerates islet vascular regression during β cell recovery and leads to increased β cell proliferation without changes in MΦ phenotype or number. Transcriptome analysis of β cells, ECs, and MΦs reveals that β cell proliferation coincides with elevated expression of extracellular matrix remodeling molecules and growth factors likely driving activation of proliferative signaling pathways in β cells. Collectively, these findings suggest a new β cell regeneration paradigm whereby coordinated interactions between intra-islet MΦs, ECs, and extracellular matrix mediate β cell self-renewal.

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Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote β cell regeneration

npj Regenerative Medicine ◽

10.1038/s41536-021-00129-z ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Diane C. Saunders ◽

Kristie I. Aamodt ◽

Tiffany M. Richardson ◽

Alexander J. Hopkirk ◽

Radhika Aramandla ◽

...

Keyword(s):

Extracellular Matrix ◽

Cell Proliferation ◽

Endothelial Cells ◽

Cell Loss ◽

Cell Regeneration ◽

Matrix Remodeling ◽

Cell Recovery ◽

Β Cells ◽

Β Cell ◽

Elevated Expression

AbstractEndogenous β cell regeneration could alleviate diabetes, but proliferative stimuli within the islet microenvironment are incompletely understood. We previously found that β cell recovery following hypervascularization-induced β cell loss involves interactions with endothelial cells (ECs) and macrophages (MΦs). Here we show that proliferative ECs modulate MΦ infiltration and phenotype during β cell loss, and recruited MΦs are essential for β cell recovery. Furthermore, VEGFR2 inactivation in quiescent ECs accelerates islet vascular regression during β cell recovery and leads to increased β cell proliferation without changes in MΦ phenotype or number. Transcriptome analysis of β cells, ECs, and MΦs reveals that β cell proliferation coincides with elevated expression of extracellular matrix remodeling molecules and growth factors likely driving activation of proliferative signaling pathways in β cells. Collectively, these findings suggest a new β cell regeneration paradigm whereby coordinated interactions between intra-islet MΦs, ECs, and extracellular matrix mediate β cell self-renewal.

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Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

Scientific Reports ◽

10.1038/s41598-021-94725-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Brenda Strutt ◽

Sandra Szlapinski ◽

Thineesha Gnaneswaran ◽

Sarah Donegan ◽

Jessica Hill ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Glucose Transporter ◽

Cell Mass ◽

Elevated Serum ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Glucose Transporter 2 ◽

Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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NF-κB activity during pancreas development regulates adult β-cell mass by modulating neonatal β-cell proliferation and apoptosis

Cell Death Discovery ◽

10.1038/s41420-020-00386-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Dror Sever ◽

Anat Hershko-Moshe ◽

Rohit Srivastava ◽

Roy Eldor ◽

Daniel Hibsher ◽

...

Keyword(s):

Cell Proliferation ◽

Developmental Stages ◽

Cell Mass ◽

Diabetes Incidence ◽

Β Cells ◽

Β Cell ◽

Cell Dysfunction ◽

Regulatory Circuit ◽

Proliferation And Apoptosis

AbstractNF-κB is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in β-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-κB in vivo, we have generated two transgenic mouse models, the ToIβ and NOD/ToIβ mice, in which NF-κB activation is specifically and conditionally inhibited in β-cells. In this study, we present a novel function of the canonical NF-κB pathway during murine islet β-cell development. Interestingly, inhibiting the NF-κB pathway in β-cells during embryogenesis, but not after birth, in both ToIβ and NOD/ToIβ mice, increased β-cell turnover, ultimately resulting in a reduced β-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-κB p65-subunit was found in neonatal β-cells, significant activation was not detected in β-cells of either adult NOD/ToIβ mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToIβ mice, inhibiting NF-κB post-weaning had no effect on the development of diabetes or β-cell dysfunction. In conclusion, our data point to NF-κB as an important component of the physiological regulatory circuit that controls the balance of β-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating β-cell mass and the development of diabetes in the mouse model of T1D.

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Is polyamine synthesis involved in the proliferative response of the intestinal epithelium to urogastrone-epidermal growth factor?

Clinical Science ◽

10.1042/cs0760595 ◽

1989 ◽

Vol 76 (6) ◽

pp. 595-598 ◽

Cited By ~ 11

Author(s):

R. A. Goodlad ◽

H. Gregory ◽

N. A. Wright

Keyword(s):

Cell Proliferation ◽

Small Intestine ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Proliferative Response ◽

Intestinal Cell ◽

Intestinal Epithelial ◽

Polyamine Synthesis ◽

Proliferative Effect ◽

Epidermal Growth

1. Intestinal epithelial cell proliferation was measured in rats maintained on total parenteral nutriton (TPN), in TPN rats given 300 μg of recombinant human epidermal growth factor (urogastrone-epidermal growth factor, URO-EGF) day−1 kg−1, and in further groups given URO-EGF and difluoromethylornithine (DFMO), an inhibitor of the enzyme ornithine decarboxylase (ODC). 2. URO-EGF significantly increased intestinal cell proliferation throughout the gastrointestinal tract. The proliferative response of the colon was particularly pronounced. 3. DFMO reduced the proliferative effect of urogastrone in the stomach and small intestine. DFMO also reduced URO-EGF-stimulated intestinal cell proliferation in the colon, but to a lesser extent. 4. It is concluded that ODC is essential for effecting the proliferative response of the stomach and small intestine to URO-EGF, but this role may be less important in the colon.

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Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00040.2013 ◽

2013 ◽

Vol 305 (1) ◽

pp. E149-E159 ◽

Cited By ~ 76

Author(s):

Rachel E. Stamateris ◽

Rohit B. Sharma ◽

Douglas A. Hollern ◽

Laura C. Alonso

Keyword(s):

Cell Proliferation ◽

Cell Mass ◽

Extended Period ◽

Time Frame ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Cyclin D2 ◽

Mass Expansion

Type 2 diabetes (T2D) is caused by relative insulin deficiency, due in part to reduced β-cell mass ( 11 , 62 ). Therapies aimed at expanding β-cell mass may be useful to treat T2D ( 14 ). Although feeding rodents a high-fat diet (HFD) for an extended period (3–6 mo) increases β-cell mass by inducing β-cell proliferation ( 16 , 20 , 53 , 54 ), evidence suggests that adult human β-cells may not meaningfully proliferate in response to obesity. The timing and identity of the earliest initiators of the rodent compensatory growth response, possible therapeutic targets to drive proliferation in refractory human β-cells, are not known. To develop a model to identify early drivers of β-cell proliferation, we studied mice during the first week of HFD exposure, determining the onset of proliferation in the context of diet-related physiological changes. Within the first week of HFD, mice consumed more kilocalories, gained weight and fat mass, and developed hyperglycemia, hyperinsulinemia, and glucose intolerance due to impaired insulin secretion. The β-cell proliferative response also began within the first week of HFD feeding. Intriguingly, β-cell proliferation increased before insulin resistance was detected. Cyclin D2 protein expression was increased in islets by day 7, suggesting it may be an early effector driving compensatory β-cell proliferation in mice. This study defines the time frame and physiology to identify novel upstream regulatory signals driving mouse β-cell mass expansion, in order to explore their efficacy, or reasons for inefficacy, in initiating human β-cell proliferation.

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Chlorogenic acid and β-glucan from highland barley grain ameliorate β cell dysfunction via inhibiting apoptosis and improving cell proliferation

Food & Function ◽

10.1039/d1fo01532j ◽

2021 ◽

Author(s):

Zehua Liu ◽

Bo Li

Keyword(s):

Cell Proliferation ◽

Chlorogenic Acid ◽

Barley Grain ◽

Whole Grain ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Active Compounds ◽

Cell Dysfunction ◽

Highland Barley

Recent studies support the view that highland barley as whole grain diet showed anti-hyperglycemic effects, while little information is available about the active compounds that could ameliorate pancreatic β cells...

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Increased vimentin in human α- and β-cells in type 2 diabetes

Journal of Endocrinology ◽

10.1530/joe-16-0588 ◽

2017 ◽

Vol 233 (3) ◽

pp. 217-227 ◽

Cited By ~ 11

Author(s):

Maaike M Roefs ◽

Françoise Carlotti ◽

Katherine Jones ◽

Hannah Wills ◽

Alexander Hamilton ◽

...

Keyword(s):

Type 2 Diabetes ◽

Epithelial To Mesenchymal Transition ◽

Islet Cells ◽

Cell Types ◽

Β Cells ◽

Β Cell ◽

Mesenchymal Transition ◽

Cell Expression

Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; P < 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.

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