Rennian Wang - Academia.edu (original) (raw)

Papers by Rennian Wang

Research paper thumbnail of Collagen IV-β1-Integrin Influences INS-1 Cell Insulin Secretion via Enhanced SNARE Protein Expression

Frontiers in Cell and Developmental Biology, Apr 28, 2022

Research paper thumbnail of <i>β</i>-Cell Receptor Tyrosine Kinases in Controlling Insulin Secretion and Exocytotic Machinery: c-Kit and Insulin Receptor

Endocrinology, Sep 19, 2018

Research paper thumbnail of Combined Insulin and Bicarbonate Therapy Elicits Cerebral Edema in a Juvenile Mouse Model of Diabetic Ketoacidosis

Pediatric Research, Mar 1, 2007

Research paper thumbnail of Expression and function of αβ1 integrins in pancretic beta (INS-1) cells

Journal of Cell Communication and Signaling, Nov 21, 2008

Research paper thumbnail of Activation of Pancreatic Stellate Cells Is Beneficial for Exocrine but Not Endocrine Cell Differentiation in the Developing Human Pancreas

Frontiers in Cell and Developmental Biology, Aug 18, 2021

Research paper thumbnail of Survivin Is Required for Beta-Cell Mass Expansion in the Pancreatic Duct-Ligated Mouse Model

Research paper thumbnail of Critical role of β1 integrin in postnatal beta-cell function and expansion

Research paper thumbnail of Inhibition of Gsk3β activity improves β-cell function in c-Kit male mice

Laboratory Investigation, Apr 1, 2012

Research paper thumbnail of A survival Kit for pancreatic beta cells: stem cell factor and c-Kit receptor tyrosine kinase

Diabetologia, Feb 3, 2015

Research paper thumbnail of Downregulation of Fas activity rescues early onset of diabetes in <i>c-Kit</i><sup><i>Wv/+</i></sup> mice

American Journal of Physiology-endocrinology and Metabolism, Mar 15, 2013

Research paper thumbnail of In vitro morphogenesis of PANC-1 cells into islet-like aggregates using RGD-covered dextran derivative surfaces

Colloids and Surfaces B: Biointerfaces, 2012

Research paper thumbnail of Fibrin improves beta (INS-1) cell function, proliferation and survival through integrin αvβ3

Acta Biomaterialia, Sep 1, 2013

Extracellular matrix (ECM)-integrin stimulation can promote beta cell differentiation, proliferat... more Extracellular matrix (ECM)-integrin stimulation can promote beta cell differentiation, proliferation and function. However, beta cells lose their insulin secretion function in response to glucose stimulation, and senesce when cultured with ECM proteins for a long time. Fibrin is a provisional ECM protein that is capable of maintaining beta cell function, yet the mechanisms by which this occurs is unknown. The present study examined how fibrin interacts with integrin receptors to promote beta cell cluster formation, proliferation and function. The rat insulinoma cell line, INS-1, was cultured on tissue-culture polystyrene, or with 2-D or 3-D fibrin gels for up to 4 weeks. Cells cultured with fibrin formed islet-like clusters and showed direct contacts with fibrin determined by scanning electron microscopy. Fibrin-cultured INS-1 cells also had significantly increased glucose-stimulated insulin secretion. A significant increase in integrin αvβ3 protein and phosphorylated FAK, Erk1/2 and Akt levels was observed in fibrin-cultured INS-1 cells, which was associated with significantly increased cell proliferation and decreased cell apoptosis. Integrin αvβ3 blockade affected INS-1 cell spreading on fibrin gels, and resulted in significantly decreased FAK phosphorylation and increased cleaved caspase-3 levels. These results show that fibrin promotes beta cell function, proliferation and survival via integrin αvβ3 interactions.

Research paper thumbnail of Glucose-Dependent Insulinotropic Polypeptide Is Expressed in Pancreatic Islet α-Cells and Promotes Insulin Secretion

Gastroenterology, May 1, 2010

Research paper thumbnail of Temporally Controlled Knockout of the β-Cell Insulin Receptor During In Utero Development Induces an Islet Compensatory Response

Canadian Journal of Diabetes, Oct 1, 2014

EFT significantly decreased (p<0.03) in each group without difference between groups (e1.7AE0.5 m... more EFT significantly decreased (p<0.03) in each group without difference between groups (e1.7AE0.5 mm vs. e1.1AE1.6 mm; p¼0.4). Conclusion: Compared to Glargine, Detemir resulted in favourable body composition changes. Both insulins favourably influenced EFT. Larger studies are needed to understand the mechanisms and potential implication of these changes.

Research paper thumbnail of Inducible Beta-Cell-Specific β1-Integrin Knockout Affects Islet Architecture, Beta-Cell Survival and Function

Canadian Journal of Diabetes, Oct 1, 2014

Research paper thumbnail of Characterization and Differentiation of Sorted Human Fetal Pancreatic ALDHhi and ALDHhi/CD133+ Cells Toward Insulin-Expressing Cells

Stem Cells and Development, Feb 15, 2018

The enzyme aldehyde dehydrogenase (ALDH) is found in developing and multipotent cell populations,... more The enzyme aldehyde dehydrogenase (ALDH) is found in developing and multipotent cell populations, and is important for the production and regulation of retinoic acid, which controls β-cell differentiation in the pancreas. The role of ALDH-expressing cells in the formation of endocrine-like cells and co-localization with the putative stem cell marker CD133 has not been examined during human pancreatic development. This study focuses on the co-expression of CD133 on ALDH cells from the human fetal pancreas (18-22 weeks of fetal age) with transcription factors (TFs) central to endocrine cell development. Fluorescence-activated cell sorting demonstrated that cells with high ALDH activity (ALDH) had increased co-expression of CD133 and endocrine-lineage TFs when compared with cells with low ALDH (ALDH) expression. Hormone-expressing (insulin, somatostatin) and ductal cells (CK19) were noted in the ALDH population, while mesenchymal (vimentin) and endothelial (CD31) markers were predominantly found in ALDH cells. Culture of sorted ALDH or ALDH/CD133 cells resulted in loss of endocrine TF, insulin, and CK19 expression. The formation of cell clusters from cultured ALDH or ALDH/CD133 cells led to restored CK19 expression and showed endocrine TFs and insulin expression. In summary, pancreatic ALDH cells contain a heterogeneous CD133-enriched population with a subset of β-cell associated markers in the developing human pancreas.

Research paper thumbnail of Postnatal knockout of beta cell insulin receptor impaired insulin secretion in male mice exposed to high-fat diet stress

Molecular and Cellular Endocrinology, 2020

The presence of insulin receptor (IR) on insulin-secreting beta cells suggests an autocrine regul... more The presence of insulin receptor (IR) on insulin-secreting beta cells suggests an autocrine regulatory role for insulin in its own signalling. Congenital beta cell-specific IR knockout (βIRKO) mouse studies have demonstrated the development of age-dependent glucose intolerance. We investigated the role of beta cell IR signalling specifically during postnatal life following undisturbed prenatal pancreatic development and maturation. We utilized a tamoxifen-inducible mouse insulin 1 promoter (MIP) driven Cre recombinase IR knockout mouse model (MIP-βIRKO) to achieve partial knockout of IR in islets and determine the functional role of beta cell IR in adult mice fed a control normal diet (ND) or 60% high-fat diet (HFD). At 24 weeks of age, MIP-βIRKO ND mice maintained glucose tolerance, insulin release, and unchanged beta cell mass when compared to control ND mice. In contrast, 24-week-old MIP-βIRKO mice demonstrated significant glucose intolerance and lower insulin release after 18 weeks of HFD feeding. A reduction in beta cell soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression, phosphorylated Akt S473 and P70S6K1 T389 , and glucose transporter 2 (GLUT2) expression were also identified in MIP-βIRKO HFD islets. Overall, the postnatal knockout of beta cell IR in HFD-fed mice resulted in decreased expression of beta cell glucose-sensing and exocytotic proteins and a reduction in intracellular signalling. These findings highlight that IR expression in the adult islet is required to maintain beta cell function under hyperglycemic stress.

Research paper thumbnail of Hepatocyte growth factor regulates the proliferation and differentiation of cartilage in developing forelimb of mouse embryos in vitro

Biomedical Research, 2004

Research paper thumbnail of Modulation of JNK and p38 Stress Activated Protein Kinases In Isolated Islets of Langerhans

Annals of Surgery, 2001

ObjectiveThe objective of this study was to determine the effects of islet isolation and cytokine... more ObjectiveThe objective of this study was to determine the effects of islet isolation and cytokine exposure on e-JUN NH2 terminal kinase (JNK) and p38 activation and whether insulin or the p38 inhibitor PD169316 could modify the response.Summary Background DataIslet transplantation exposes the cells of the graft to a variety of stressful stimuli that could promote β-cell death and lead to graft failure.MethodsIslets from canine (n = 12) and cadaveric human (n = 6) pancreata were isolated and purified. Islets were cultured in CMRL 1066 with and without 100 ng/ml insulin. The response to cytokine stimulation with tumor necrosis factor (TNF)α and IL-1β and the p38 inhibitor PD169316 was also observed. Islet lysates were analyzed by Western blotting for total and phosphorylated JNK and p38 content. Apoptosis was assessed by TdT-mediated dUTP nick end labeling (TUNEL) assay and by a specific cell death enzyme-linked immunosorbant assay (ELISA).ResultsIn unstimulated islets, JNK activity was highest immediately following isolation, declining over 3 days to a low baseline level. The activity of p38 was lowest immediately after isolation, increasing progressively with time. The addition of insulin resulted in a more rapid decline in JNK activity, as opposed to p38, which showed no decrease in phosphorylation in response to insulin. In the cytokine stimulation studies, IL-1β stimulated p38 activation in a dose dependent manner, while JNK was relatively unaffected. PD169316 (100μg/ml) was able to inhibit p38 activation in response to the isolation procedure as well as cytokine stimulation. Apoptotic activity was highest 24 hours after isolation, and was significantly reduced when islets were maintained in insulin-supplemented medium.ConclusionsInhibition of the stress-activated protein kinase (SAPK) pathways may be important for the maintenance of islet cell survival following islet isolation for transplantation. This study supports an autocrine role of insulin in this process.

Research paper thumbnail of The Structural Integrity of the Islet In Vitro

Pancreas, Oct 1, 1999

ABSTRACT The purpose of this study was to examine the effect of incubation temperature on the str... more ABSTRACT The purpose of this study was to examine the effect of incubation temperature on the structural integrity of the islet during culture. Islets were isolated from the pancreas of the Syrian golden hamster and cultured in a collagen gel for &lt;= 12 days at 24[degrees]C or 37[degrees]C. At 24[degrees]C, cells in the islet periphery died, leading to a complete disintegration of the mantle region in 37.4 +/- 5.6% of the islets. In comparison, at 37[degrees]C, few islets exhibited mantle disintegration (p &lt;0.001). Insulin immunoreactivity was distributed nonhomogeneously in islets at 24[degrees]C, and the intensity of the staining, by using a Semiquantitative scale (0-3), was + 1. Islets cultured at 37[degrees]C had a normal homogeneous distribution of insulin immunoreactivity with a score of +3. As the pancreas is a complex gland composed of different cell types, and cell-cell interactions are known to be important in the maintenance of cell survival, additional experiments were repeated to include the coculture of islets with duct epithelial cells. The proportion of islets that developed mantle disintegration was now reduced to 2.5 +/- 0.3% (p &lt;0.001). comparable to that seen at 37[degrees]C. Similar results were obtained for islets cultured in the presence of duct-conditioned medium (DCM). Together with the preservation of the islet mantle, islets cultured in the presence of duct epithelial cells or DCM had a normal homogeneous distribution of insulin immunoreactivity, with a staining intensity of +3. We conclude that incubation temperature has a profound effect on the structural integrity of islets, and that the detrimental effects of low temperature culture can be mitigated by coculture of islets with secretory products derived from pancreatic ductal cells. These data provide evidence for a trophic relation between pancreatic islets and ductal epithelium.

Research paper thumbnail of Collagen IV-β1-Integrin Influences INS-1 Cell Insulin Secretion via Enhanced SNARE Protein Expression

Frontiers in Cell and Developmental Biology, Apr 28, 2022

Research paper thumbnail of <i>β</i>-Cell Receptor Tyrosine Kinases in Controlling Insulin Secretion and Exocytotic Machinery: c-Kit and Insulin Receptor

Endocrinology, Sep 19, 2018

Research paper thumbnail of Combined Insulin and Bicarbonate Therapy Elicits Cerebral Edema in a Juvenile Mouse Model of Diabetic Ketoacidosis

Pediatric Research, Mar 1, 2007

Research paper thumbnail of Expression and function of αβ1 integrins in pancretic beta (INS-1) cells

Journal of Cell Communication and Signaling, Nov 21, 2008

Research paper thumbnail of Activation of Pancreatic Stellate Cells Is Beneficial for Exocrine but Not Endocrine Cell Differentiation in the Developing Human Pancreas

Frontiers in Cell and Developmental Biology, Aug 18, 2021

Research paper thumbnail of Survivin Is Required for Beta-Cell Mass Expansion in the Pancreatic Duct-Ligated Mouse Model

Research paper thumbnail of Critical role of β1 integrin in postnatal beta-cell function and expansion

Research paper thumbnail of Inhibition of Gsk3β activity improves β-cell function in c-Kit male mice

Laboratory Investigation, Apr 1, 2012

Research paper thumbnail of A survival Kit for pancreatic beta cells: stem cell factor and c-Kit receptor tyrosine kinase

Diabetologia, Feb 3, 2015

Research paper thumbnail of Downregulation of Fas activity rescues early onset of diabetes in <i>c-Kit</i><sup><i>Wv/+</i></sup> mice

American Journal of Physiology-endocrinology and Metabolism, Mar 15, 2013

Research paper thumbnail of In vitro morphogenesis of PANC-1 cells into islet-like aggregates using RGD-covered dextran derivative surfaces

Colloids and Surfaces B: Biointerfaces, 2012

Research paper thumbnail of Fibrin improves beta (INS-1) cell function, proliferation and survival through integrin αvβ3

Acta Biomaterialia, Sep 1, 2013

Extracellular matrix (ECM)-integrin stimulation can promote beta cell differentiation, proliferat... more Extracellular matrix (ECM)-integrin stimulation can promote beta cell differentiation, proliferation and function. However, beta cells lose their insulin secretion function in response to glucose stimulation, and senesce when cultured with ECM proteins for a long time. Fibrin is a provisional ECM protein that is capable of maintaining beta cell function, yet the mechanisms by which this occurs is unknown. The present study examined how fibrin interacts with integrin receptors to promote beta cell cluster formation, proliferation and function. The rat insulinoma cell line, INS-1, was cultured on tissue-culture polystyrene, or with 2-D or 3-D fibrin gels for up to 4 weeks. Cells cultured with fibrin formed islet-like clusters and showed direct contacts with fibrin determined by scanning electron microscopy. Fibrin-cultured INS-1 cells also had significantly increased glucose-stimulated insulin secretion. A significant increase in integrin αvβ3 protein and phosphorylated FAK, Erk1/2 and Akt levels was observed in fibrin-cultured INS-1 cells, which was associated with significantly increased cell proliferation and decreased cell apoptosis. Integrin αvβ3 blockade affected INS-1 cell spreading on fibrin gels, and resulted in significantly decreased FAK phosphorylation and increased cleaved caspase-3 levels. These results show that fibrin promotes beta cell function, proliferation and survival via integrin αvβ3 interactions.

Research paper thumbnail of Glucose-Dependent Insulinotropic Polypeptide Is Expressed in Pancreatic Islet α-Cells and Promotes Insulin Secretion

Gastroenterology, May 1, 2010

Research paper thumbnail of Temporally Controlled Knockout of the β-Cell Insulin Receptor During In Utero Development Induces an Islet Compensatory Response

Canadian Journal of Diabetes, Oct 1, 2014

EFT significantly decreased (p<0.03) in each group without difference between groups (e1.7AE0.5 m... more EFT significantly decreased (p<0.03) in each group without difference between groups (e1.7AE0.5 mm vs. e1.1AE1.6 mm; p¼0.4). Conclusion: Compared to Glargine, Detemir resulted in favourable body composition changes. Both insulins favourably influenced EFT. Larger studies are needed to understand the mechanisms and potential implication of these changes.

Research paper thumbnail of Inducible Beta-Cell-Specific β1-Integrin Knockout Affects Islet Architecture, Beta-Cell Survival and Function

Canadian Journal of Diabetes, Oct 1, 2014

Research paper thumbnail of Characterization and Differentiation of Sorted Human Fetal Pancreatic ALDHhi and ALDHhi/CD133+ Cells Toward Insulin-Expressing Cells

Stem Cells and Development, Feb 15, 2018

The enzyme aldehyde dehydrogenase (ALDH) is found in developing and multipotent cell populations,... more The enzyme aldehyde dehydrogenase (ALDH) is found in developing and multipotent cell populations, and is important for the production and regulation of retinoic acid, which controls β-cell differentiation in the pancreas. The role of ALDH-expressing cells in the formation of endocrine-like cells and co-localization with the putative stem cell marker CD133 has not been examined during human pancreatic development. This study focuses on the co-expression of CD133 on ALDH cells from the human fetal pancreas (18-22 weeks of fetal age) with transcription factors (TFs) central to endocrine cell development. Fluorescence-activated cell sorting demonstrated that cells with high ALDH activity (ALDH) had increased co-expression of CD133 and endocrine-lineage TFs when compared with cells with low ALDH (ALDH) expression. Hormone-expressing (insulin, somatostatin) and ductal cells (CK19) were noted in the ALDH population, while mesenchymal (vimentin) and endothelial (CD31) markers were predominantly found in ALDH cells. Culture of sorted ALDH or ALDH/CD133 cells resulted in loss of endocrine TF, insulin, and CK19 expression. The formation of cell clusters from cultured ALDH or ALDH/CD133 cells led to restored CK19 expression and showed endocrine TFs and insulin expression. In summary, pancreatic ALDH cells contain a heterogeneous CD133-enriched population with a subset of β-cell associated markers in the developing human pancreas.

Research paper thumbnail of Postnatal knockout of beta cell insulin receptor impaired insulin secretion in male mice exposed to high-fat diet stress

Molecular and Cellular Endocrinology, 2020

The presence of insulin receptor (IR) on insulin-secreting beta cells suggests an autocrine regul... more The presence of insulin receptor (IR) on insulin-secreting beta cells suggests an autocrine regulatory role for insulin in its own signalling. Congenital beta cell-specific IR knockout (βIRKO) mouse studies have demonstrated the development of age-dependent glucose intolerance. We investigated the role of beta cell IR signalling specifically during postnatal life following undisturbed prenatal pancreatic development and maturation. We utilized a tamoxifen-inducible mouse insulin 1 promoter (MIP) driven Cre recombinase IR knockout mouse model (MIP-βIRKO) to achieve partial knockout of IR in islets and determine the functional role of beta cell IR in adult mice fed a control normal diet (ND) or 60% high-fat diet (HFD). At 24 weeks of age, MIP-βIRKO ND mice maintained glucose tolerance, insulin release, and unchanged beta cell mass when compared to control ND mice. In contrast, 24-week-old MIP-βIRKO mice demonstrated significant glucose intolerance and lower insulin release after 18 weeks of HFD feeding. A reduction in beta cell soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression, phosphorylated Akt S473 and P70S6K1 T389 , and glucose transporter 2 (GLUT2) expression were also identified in MIP-βIRKO HFD islets. Overall, the postnatal knockout of beta cell IR in HFD-fed mice resulted in decreased expression of beta cell glucose-sensing and exocytotic proteins and a reduction in intracellular signalling. These findings highlight that IR expression in the adult islet is required to maintain beta cell function under hyperglycemic stress.

Research paper thumbnail of Hepatocyte growth factor regulates the proliferation and differentiation of cartilage in developing forelimb of mouse embryos in vitro

Biomedical Research, 2004

Research paper thumbnail of Modulation of JNK and p38 Stress Activated Protein Kinases In Isolated Islets of Langerhans

Annals of Surgery, 2001

ObjectiveThe objective of this study was to determine the effects of islet isolation and cytokine... more ObjectiveThe objective of this study was to determine the effects of islet isolation and cytokine exposure on e-JUN NH2 terminal kinase (JNK) and p38 activation and whether insulin or the p38 inhibitor PD169316 could modify the response.Summary Background DataIslet transplantation exposes the cells of the graft to a variety of stressful stimuli that could promote β-cell death and lead to graft failure.MethodsIslets from canine (n = 12) and cadaveric human (n = 6) pancreata were isolated and purified. Islets were cultured in CMRL 1066 with and without 100 ng/ml insulin. The response to cytokine stimulation with tumor necrosis factor (TNF)α and IL-1β and the p38 inhibitor PD169316 was also observed. Islet lysates were analyzed by Western blotting for total and phosphorylated JNK and p38 content. Apoptosis was assessed by TdT-mediated dUTP nick end labeling (TUNEL) assay and by a specific cell death enzyme-linked immunosorbant assay (ELISA).ResultsIn unstimulated islets, JNK activity was highest immediately following isolation, declining over 3 days to a low baseline level. The activity of p38 was lowest immediately after isolation, increasing progressively with time. The addition of insulin resulted in a more rapid decline in JNK activity, as opposed to p38, which showed no decrease in phosphorylation in response to insulin. In the cytokine stimulation studies, IL-1β stimulated p38 activation in a dose dependent manner, while JNK was relatively unaffected. PD169316 (100μg/ml) was able to inhibit p38 activation in response to the isolation procedure as well as cytokine stimulation. Apoptotic activity was highest 24 hours after isolation, and was significantly reduced when islets were maintained in insulin-supplemented medium.ConclusionsInhibition of the stress-activated protein kinase (SAPK) pathways may be important for the maintenance of islet cell survival following islet isolation for transplantation. This study supports an autocrine role of insulin in this process.

Research paper thumbnail of The Structural Integrity of the Islet In Vitro

Pancreas, Oct 1, 1999

ABSTRACT The purpose of this study was to examine the effect of incubation temperature on the str... more ABSTRACT The purpose of this study was to examine the effect of incubation temperature on the structural integrity of the islet during culture. Islets were isolated from the pancreas of the Syrian golden hamster and cultured in a collagen gel for &lt;= 12 days at 24[degrees]C or 37[degrees]C. At 24[degrees]C, cells in the islet periphery died, leading to a complete disintegration of the mantle region in 37.4 +/- 5.6% of the islets. In comparison, at 37[degrees]C, few islets exhibited mantle disintegration (p &lt;0.001). Insulin immunoreactivity was distributed nonhomogeneously in islets at 24[degrees]C, and the intensity of the staining, by using a Semiquantitative scale (0-3), was + 1. Islets cultured at 37[degrees]C had a normal homogeneous distribution of insulin immunoreactivity with a score of +3. As the pancreas is a complex gland composed of different cell types, and cell-cell interactions are known to be important in the maintenance of cell survival, additional experiments were repeated to include the coculture of islets with duct epithelial cells. The proportion of islets that developed mantle disintegration was now reduced to 2.5 +/- 0.3% (p &lt;0.001). comparable to that seen at 37[degrees]C. Similar results were obtained for islets cultured in the presence of duct-conditioned medium (DCM). Together with the preservation of the islet mantle, islets cultured in the presence of duct epithelial cells or DCM had a normal homogeneous distribution of insulin immunoreactivity, with a staining intensity of +3. We conclude that incubation temperature has a profound effect on the structural integrity of islets, and that the detrimental effects of low temperature culture can be mitigated by coculture of islets with secretory products derived from pancreatic ductal cells. These data provide evidence for a trophic relation between pancreatic islets and ductal epithelium.