scholarly journals Genetic deletion of Urocortin 3 does not prevent functional maturation of beta cells

2020 ◽  
Vol 246 (1) ◽  
pp. 69-78
Author(s):  
Jessica L Huang ◽  
Sharon Lee ◽  
Pelle Hoek ◽  
Talitha van der Meulen ◽  
Richard Van ◽  
...  
Keyword(s):  
Stem Cells ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Mass ◽  
Cell Maturation ◽  
Cell Dedifferentiation ◽  
Beta Cell Maturation ◽  
Urocortin 3 ◽  
Genetic Deletion ◽  
Mature Beta Cells

There is great interest in generating functionally mature beta cells from stem cells, as loss of functional beta cell mass contributes to the pathophysiology of diabetes. Identifying markers of beta cell maturity is therefore very helpful for distinguishing stem cells that have been successfully differentiated into fully mature beta cells from stem cells that did not. Urocortin 3 (UCN3) is a peptide hormone whose expression is associated with the acquisition of functional maturity in beta cells. The onset of its expression occurs after other beta cell maturity markers are already expressed and its loss marks the beginning of beta cell dedifferentiation. Its expression pattern is therefore tightly correlated with beta cell maturity. While this makes UCN3 an excellent marker of beta cell maturity, it is not established whether UCN3 is required for beta cell maturation. Here, we compared gene expression and function of beta cells from Ucn3-null mice relative to WT mice to determine whether beta cells are functionally mature in the absence of UCN3. Our results show that genetic deletion of Ucn3 does not cause a loss of beta cell maturity or an increase in beta cell dedifferentiation. Furthermore, virgin beta cells, first identified as insulin-expressing, UCN3-negative beta cells, can still be detected at the islet periphery in Ucn3-null mice. Beta cells from Ucn3-null mice also exhibit normal calcium response when exposed to high glucose. Collectively, these observations indicate that UCN3 is an excellent mature beta cell marker that is nevertheless not necessary for beta cell maturation.

scholarly journals Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3

2012 ◽  
Vol 30 (3) ◽  
pp. 261-264 ◽  
Author(s):  
Barak Blum ◽  
Siniša Hrvatin ◽  
Christian Schuetz ◽  
Claire Bonal ◽  
Alireza Rezania ◽  
...  
Keyword(s):  
Beta Cell ◽  
Cell Maturation ◽  
Beta Cell Maturation ◽  
Urocortin 3 ◽  
Glucose Threshold

scholarly journals An overview on small molecule-induced differentiation of mesenchymal stem cells into beta cells for diabetic therapy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Nimshitha Pavathuparambil Abdul Manaph ◽  
Kisha N. Sivanathan ◽  
Jodie Nitschke ◽  
Xin-Fu Zhou ◽  
Patrick T. Coates ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Beta Cell ◽  
Small Molecules ◽  
Beta Cells ◽  
Small Molecule ◽  
Pancreatic Beta Cells ◽  
Mature Beta Cells

Abstract The field of regenerative medicine provides enormous opportunities for generating beta cells from different stem cell sources for cellular therapy. Even though insulin-secreting cells can be generated from a variety of stem cell types like pluripotent stem cells and embryonic stem cells, the ideal functional cells should be generated from patients’ own cells and expanded to considerable levels by non-integrative culture techniques. In terms of the ease of isolation, plasticity, and clinical translation to generate autologous cells, mesenchymal stem cell stands superior. Furthermore, small molecules offer a great advantage in terms of generating functional beta cells from stem cells. Research suggests that most of the mesenchymal stem cell-based protocols to generate pancreatic beta cells have small molecules in their cocktail. However, most of the protocols generate cells that mimic the characteristics of human beta cells, thereby generating “beta cell-like cells” as opposed to mature beta cells. Diabetic therapy becomes feasible only when there are robust, functional, and safe cells for replacing the damaged or lost beta cells. In this review, we discuss the current protocols used to generate beta cells from mesenchymal cells, with emphasis on small molecule-mediated conversion into insulin-producing beta cell-like cells. Our data and the data presented from the references within this review would suggest that although mesenchymal stem cells are an attractive cell type for cell therapy they are not readily converted into functional mature beta cells.

scholarly journals Neonatal Treatment With Beta-Cell Stimulatory Agents Reduces the Incidence of Diabetes in BB Rats

2000 ◽  
Vol 1 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Karsten Buschard ◽  
Troels Bock ◽  
Charlotte R. Pedersen ◽  
Susanne V. Hansen ◽  
Kim Aaen ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Immunological Tolerance ◽  
Cell Maturation ◽  
Diabetes Incidence ◽  
Neonatal Treatment ◽  
Bb Rats ◽  
Beta Cell Maturation ◽  
Diabetes Development

The aim of the study was to investigate whether various beta-cell stimulatory drugs, given neonatally, influence the incidence of diabetes in BB rats. Newborn BB rats were treated twice daily for 6 days and diabetes development was observed during the following 200-day study period. Compared to a diabetes incidence of 63.8% in 163 control BB rats which received saline or were untreated, the percentage of experimental BB rats that developed diabetes was as follows in the different subgroups: arginineglucose: 47% (n= 73,p< 0.02); glucagon: 37% (n= 93,p< 0.0001); tolbutamide-glucose: 36% (n= 58,p< 0.0005); and theophylline-glucose: 39% (n= 41,p< 0.005). A long-term arginine-glucose treatment was not superior to the shorter neonatal treatment. Histological examination revealed a higher degree of insulitis in diabetic than in non-diabetic animals but no difference according to the kind of treatment was observed. Finally, we found that the diabetes incidence in BB rats was higher in the first litter compared to subsequent litters (p= 0.04). Thus, neonatal treatment with various beta-cell stimulatory agents reduces diabetes incidence in BB rats. The theory behind the study, that the treatment accelerates beta-cell maturation leading to increased immunological tolerance towards beta cells, is discussed.

scholarly journals Gastrin producing syngeneic mesenchymal stem cells protect non-obese diabetic mice from type 1 diabetes

2021 ◽  
Author(s):  
Marie-Claude Gaudreau ◽  
Radhika R Gudi ◽  
Gongbo Li ◽  
BENJAMIN JOHNSON ◽  
Chenthamarakshan Vasu
Keyword(s):  
Stem Cells ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Disease Progression ◽  
Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Cell Phenotype ◽  
Therapeutic Effects

Progressive destruction of pancreatic islet beta-cells by immune cells is the primary feature of type 1 diabetes (T1D) and therapies that can restore the functional beta-cell mass are needed to alleviate disease progression. Here, we report the use of mesenchymal stromal/stem cells (MSCs) for the production and delivery of Gastrin, a peptide-hormone which is produced by intestinal cells and fetal islets and can increase beta-Cell mass, to promote protection from T1D. A single injection of syngeneic MSCs that were engineered to express Gastrin (Gastrin-MSCs) caused a profound delay in hyperglycemia in non-obese diabetic (NOD) mice compared to engineered control-MSCs. Similar treatment of early-hyperglycemic mice caused restoration of euglycemia for a significant duration, and these therapeutic effects were associated with protection of, and/or increase in, insulin producing islets and less severe insulitis. While the overall immune cell phenotype was not affected profoundly, pancreatic lymph node cells from Gastrin-MSC treated mice, upon ex vivo challenge with self-antigen, showed a Th2 and Th17 bias, and diminished the diabetogenic property in NOD-Rag1 deficient mice suggesting a disease protective immune modulation upon Gastrin-MSC treatment. Overall, this study shows the potential of production and delivery of Gastrin in vivo, by MSCs, in protecting insulin producing beta-cells and ameliorating the disease progression in T1D.

scholarly journals Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet?

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 191
Author(s):  
Stephanie Bourgeois ◽  
Toshiaki Sawatani ◽  
Annelore Van Mulders ◽  
Nico De Leu ◽  
Yves Heremans ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Beta Cell ◽  
Beta Cells ◽  
Pluripotent Stem Cells ◽  
Pancreatic Beta Cells ◽  
Embryonic Stem ◽  
Current Status ◽  
Attractive Alternative ◽  
Mature Beta Cells

Diabetes mellitus is a pandemic metabolic disorder that results from either the autoimmune destruction or the dysfunction of insulin-producing pancreatic beta cells. A promising cure is beta cell replacement through the transplantation of islets of Langerhans. However, donor shortage hinders the widespread implementation of this therapy. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, represent an attractive alternative beta cell source for transplantation. Although major advances over the past two decades have led to the generation of stem cell-derived beta-like cells that share many features with genuine beta cells, producing fully mature beta cells remains challenging. Here, we review the current status of beta cell differentiation protocols and highlight specific challenges that are associated with producing mature beta cells. We address the challenges and opportunities that are offered by monogenic forms of diabetes. Finally, we discuss the remaining hurdles for clinical application of stem cell-derived beta cells and the status of ongoing clinical trials.

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.

scholarly journals Mechanisms involved in the beta-cell mass increase induced by chronic sucrose feeding to normal rats

2002 ◽  
Vol 174 (2) ◽  
pp. 225-231 ◽  
Author(s):  
H Del Zotto ◽  
CL Gomez Dumm ◽  
S Drago ◽  
A Fortino ◽  
GC Luna ◽  
...  
Keyword(s):  
Body Weight ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Serum Glucose ◽  
Beta Cell Apoptosis ◽  
Cell Replication ◽  
Replication Rate ◽  
Endocrine Tissue

The aim of the present study was to clarify the mechanisms by which a sucrose-rich diet (SRD) produces an increase in the pancreatic beta-cell mass in the rat. Normal Wistar rats were fed for 30 weeks either an SRD (SRD rats; 63% wt/wt), or the same diet but with starch instead of sucrose in the same proportion (CD rats). We studied body weight, serum glucose and triacylglycerol levels, endocrine tissue and beta-cell mass, beta-cell replication rate (proliferating cell nuclear antigen; PCNA), islet neogenesis (cytokeratin immunostaining) and beta-cell apoptosis (propidium iodide). Body weight (g) recorded in the SRD rats was significantly (P<0.05) larger than that of the CD group (556.0+/-8.3 vs 470.0+/-13.1). Both serum glucose and triacylglycerol levels (mmol/l) were also significantly higher (P<0.05) in SRD than in CD rats (serum glucose, 8.11+/-0.14 vs 6.62+/-0.17; triacylglycerol, 1.57+/-0.18 vs 0.47+/-0.04). The number of pancreatic islets per unit area increased significantly (P<0.05) in SRD rats (3.29+/-0.1 vs 2.01+/-0.2). A significant increment (2.6 times) in the mass of endocrine tissue was detected in SRD animals, mainly due to an increase in the beta-cell mass (P=0.0025). The islet cell replication rate, measured as the percentage of PCNA-labelled beta cells increased 6.8 times in SRD rats (P<0.03). The number of apoptotic cells in the endocrine pancreas decreased significantly (three times) in the SRD animals (P=0.03). The cytokeratin-positive area did not show significant differences between CD and SRD rats. The increase of beta-cell mass induced by SRD was accomplished by an enhanced replication of beta cells together with a decrease in the rate of beta-cell apoptosis, without any evident participation of islet neogenesis. This pancreatic reaction was unable to maintain serum glucose levels of these rats at the level measured in CD animals.

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