Can Functionally Mature Islet β-Cells Be Derived from Pluripotent Stem Cells? – A Step Towards Ready-To-Use β-Cells in Type 1 Diabetes

2020 ◽  
Vol 15 ◽  
Author(s):  
Bishnu K Khand ◽  
Ramesh R Bhonde
Keyword(s):  
Stem Cells ◽  
Type 1 Diabetes ◽  
Pluripotent Stem Cells ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

: Pluripotent Stem Cells [PSCs] are emerging as an excellent cellular source for treatment of many degenerative diseases such as diabetes, ischemic heart failure, Alzheimer’s disease. PSC-derived pancreatic islet β-cells appear to be as a promising therapy for type 1 diabetes patients with impaired β-cell function. Several protocols have been developed to derive β-cells from PSCs. However, these protocols produce β-like cells that show low glucose stimulated insulin secretion [GSIS] function and mirror GSIS profile of functionally immature neonatal β-cells. Several studies have documented a positive correlation between the sirtuins [a family of ageing-related proteins] and the GSIS function of adult β-cells. We are of the view that GSIS function of PSC-derived β-like cells could be enhanced by improving the function of sirtuins in them. Studying the sirtuin expression and activation pattern during the β-cell development and inclusion of the sirtuin activator and inhibitor cocktail [specific to a developmental stage] in the present protocols may help us derive functionally mature, ready-to-use β-cells in-vitro making them suitable for transplantation in type 1 diabetes.

Vitamin D supplementation induces CatG-mediated CD4+ T cell inactivation and restores pancreatic beta-cell function in mice with type 1 diabetes

2021 ◽  
Author(s):  
Xiaoyang Lai ◽  
Xuyang Liu ◽  
Xia Cai ◽  
Fang Zou
Keyword(s):  
Vitamin D ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function

Type 1 diabetes (T1D) is a chronic autoimmune disease accompanied by the immune-mediated destruction of pancreatic β-cells. In this study, we aimed to explore the regulatory effects of Vitamin D (VD) supplementation on pancreatic β-cell function by altering the expression of bioinformatically identified cathepsin G (CatG) in T1D model mice. A T1D mouse model was established in non-obese diabetic (NOD) mice, and their islets were isolated and purified. Pancreatic mononuclear cells (MNCs) were collected, from which CD4+ T cells were isolated. The levels of interleukin (IL)-2, IL-10, tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ) in the supernatant of mouse pancreatic tissue homogenate were assessed using ELISA. Immunohistochemistry and TUNEL staining were conducted to evaluate the effects of VD supplementation on pancreatic tissues of T1D mice. The pancreatic beta-cell line MIN6 was used for in vitro substantiation of findings in vivo. VD supplementation reduced glucose levels and improved glucose tolerance in T1D mice. Further, VD supplementation improved pancreatic β-cell function and suppressed immunological and inflammatory reactions in the T1D mice. We documented overexpression of CatG in diabetes tissue samples, and then showed that VD supplementation normalized the islet immune microenvironment through down-regulating CatG expression in T1D mice. Experiments in vitro subsequently demonstrated that VD supplementation impeded CD4+ T activation by down-regulating CatG expression, and thereby enhanced pancreatic β-cell function. Results of the present study elucidated that VD supplementation can down-regulate the expression of CatG and inhibit CD4+ T cell activation, thereby improving β-cell function in T1D.

scholarly journals A20 Inhibits β-Cell Apoptosis by Multiple Mechanisms and Predicts Residual β-Cell Function in Type 1 Diabetes

2016 ◽  
Vol 30 (1) ◽  
pp. 48-61 ◽  
Author(s):  
Makiko Fukaya ◽  
Caroline A. Brorsson ◽  
Kira Meyerovich ◽  
Leen Catrysse ◽  
Diane Delaroche ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Type 1 Diabetes ◽  
Cell Function ◽  
Nucleotide Polymorphism ◽  
Β Cells ◽  
Β Cell ◽  
Single Nucleotide ◽  
Β Cell Function ◽  
Diabetes Outcome

Abstract Activation of the transcription factor nuclear factor kappa B (NFkB) contributes to β-cell death in type 1 diabetes (T1D). Genome-wide association studies have identified the gene TNF-induced protein 3 (TNFAIP3), encoding for the zinc finger protein A20, as a susceptibility locus for T1D. A20 restricts NF-κB signaling and has strong antiapoptotic activities in β-cells. Although the role of A20 on NF-κB inhibition is well characterized, its other antiapoptotic functions are largely unknown. By studying INS-1E cells and rat dispersed islet cells knocked down or overexpressing A20 and islets isolated from the β-cell-specific A20 knockout mice, we presently demonstrate that A20 has broader effects in β-cells that are not restricted to inhibition of NF-κB. These involves, suppression of the proapoptotic mitogen-activated protein kinase c-Jun N-terminal kinase (JNK), activation of survival signaling via v-akt murine thymoma viral oncogene homolog (Akt) and consequently inhibition of the intrinsic apoptotic pathway. Finally, in a cohort of T1D children, we observed that the risk allele of the rs2327832 single nucleotide polymorphism of TNFAIP3 predicted lower C-peptide and higher hemoglobin A1c (HbA1c) levels 12 months after disease onset, indicating reduced residual β-cell function and impaired glycemic control. In conclusion, our results indicate a critical role for A20 in the regulation of β-cell survival and unveil novel mechanisms by which A20 controls β-cell fate. Moreover, we identify the single nucleotide polymorphism rs2327832 of TNFAIP3 as a possible prognostic marker for diabetes outcome in children with T1D.

scholarly journals Preventing type 1 diabetes in childhood

Science ◽  
2021 ◽  
Vol 373 (6554) ◽  
pp. 506-510 ◽  
Author(s):  
Colin M. Dayan ◽  
Rachel E. J. Besser ◽  
Richard A. Oram ◽  
William Hagopian ◽  
Manu Vatish ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Large Scale ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Genetic Risk Assessment ◽  
Recent Success ◽  
Β Cell Function ◽  
Cell Preservation

Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β cells of the pancreas are destroyed by T lymphocytes. Recent studies have demonstrated that monitoring for pancreatic islet autoantibodies, combined with genetic risk assessment, can identify most children who will develop T1D when they still have sufficient β cell function to control glucose concentrations without the need for insulin. In addition, there has been recent success in secondary prevention using immunotherapy to delay the progression of preclinical disease, and primary prevention approaches to inhibiting the initiating autoimmune process have entered large-scale clinical trials. By changing the focus of T1D management from late diagnosis and insulin replacement to early diagnosis and β cell preservation, we can anticipate a future without the need for daily insulin injections for children with T1D.

scholarly journals Differentiation of nestin-positive cells derived from bone marrow into pancreatic endocrine and ductal cells in vitro

2011 ◽  
Vol 209 (2) ◽  
pp. 193-201 ◽  
Author(s):  
Anna Milanesi ◽  
Jang-Won Lee ◽  
Qijin Xu ◽  
Laura Perin ◽  
John S Yu
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Type 1 Diabetes ◽  
Pancreatic Islet ◽  
Bone Marrow Stem Cells ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2

Promising results of pancreatic islet transplantation to treat type 1 diabetes mellitus, combined with severe shortage of donor pancreata, have spurred efforts to generate pancreatic islet-like cells and insulin-producing β-cells from various progenitor populations. In this study, we show for the first time that multipotent nestin-positive stem cells selected from rat bone marrow can be differentiated into pancreatic ductal and insulin-producing β-cells in vitro. We report an effective multistep protocol in a serum-free system, which could efficiently induce β-cell differentiation from multipotent nestin-positive bone marrow stem cells. To enhance the induction and differentiation toward pancreatic lineage we used trichostatin A, an important regulator of chromatin remodeling, and 5-aza 2′ deoxycytidine, an inhibitor of DNA methylase. All-trans retinoic acid was then utilized to promote pancreatic differentiation. We sequentially induced important transcription factor genes, such as Pdx1, Ngn3, and Pax6, following the in vivo development timeline of the pancreas in rats. Furthermore, in the final stage with the presence of nicotinamide, the induced cells expressed islet and ductal specific markers. The differentiated cells not only expressed insulin and glucose transporter 2, but also displayed a glucose-responsive secretion of the hormone. Our results delineate a new model system to study islet neogenesis and possible pharmaceutical targets. Nestin-positive bone marrow stem cells may be therapeutically relevant for β-cell replacement in type 1 diabetes.

scholarly journals 100 years post insulin: immunotherapy as the next frontier in Type 1 Diabetes

2021 ◽  
Author(s):  
James A Pearson ◽  
Eoin F McKinney ◽  
Lucy S K Walker
Keyword(s):  
Type 1 Diabetes ◽  
Autoimmune Disease ◽  
Turning Point ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Selection Of ◽  
New Onset

Abstract Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell-mediated destruction of the insulin-producing β cells in the pancreas. Similar to other autoimmune diseases, the incidence of T1D is increasing globally. The discovery of insulin 100 years ago dramatically changed the outlook for people with T1D, preventing this from being a fatal condition. As we celebrate the centenary of this milestone, therapeutic options for T1D are once more at a turning point. Years of effort directed at developing immunotherapies are finally starting to pay off, with signs of progress in new onset and even preventative settings. Here we review a selection of immunotherapies that have shown promise in preserving β cell function and highlight future considerations for immunotherapy in the T1D setting.

scholarly journals In vivo imaging of β-cell function reveals glucose-mediated heterogeneity of β-cell functional development

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jia Zhao ◽  
Weijian Zong ◽  
Yiwen Zhao ◽  
Dongzhou Gou ◽  
Shenghui Liang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
In Vivo Imaging ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Functional Development ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

How pancreatic β-cells acquire function in vivo is a long-standing mystery due to the lack of technology to visualize β-cell function in living animals. Here, we applied a high-resolution two-photon light-sheet microscope for the first in vivo imaging of Ca2+activity of every β-cell in Tg (ins:Rcamp1.07) zebrafish. We reveal that the heterogeneity of β-cell functional development in vivo occurred as two waves propagating from the islet mantle to the core, coordinated by islet vascularization. Increasing amounts of glucose induced functional acquisition and enhancement of β-cells via activating calcineurin/nuclear factor of activated T-cells (NFAT) signaling. Conserved in mammalians, calcineurin/NFAT prompted high-glucose-stimulated insulin secretion of neonatal mouse islets cultured in vitro. However, the reduction in low-glucose-stimulated insulin secretion was dependent on optimal glucose but independent of calcineurin/NFAT. Thus, combination of optimal glucose and calcineurin activation represents a previously unexplored strategy for promoting functional maturation of stem cell-derived β-like cells in vitro.

scholarly journals Pericytes contribute to the islet basement membranes to promote beta-cell gene expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lina Sakhneny ◽  
Alona Epshtein ◽  
Limor Landsman
Keyword(s):  
Gene Expression ◽  
Cell Function ◽  
Basement Membranes ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Cell Clustering ◽  
Β Cell Function ◽  
Cell Gene Expression ◽  
Glucose Stimulated Insulin Secretion

Abstractβ-Cells depend on the islet basement membrane (BM). While some islet BM components are produced by endothelial cells (ECs), the source of others remains unknown. Pancreatic pericytes directly support β-cells through mostly unidentified secreted factors. Thus, we hypothesized that pericytes regulate β-cells through the production of BM components. Here, we show that pericytes produce multiple components of the mouse pancreatic and islet interstitial and BM matrices. Several of the pericyte-produced ECM components were previously implicated in β-cell physiology, including collagen IV, laminins, proteoglycans, fibronectin, nidogen, and hyaluronan. Compared to ECs, pancreatic pericytes produce significantly higher levels of α2 and α4 laminin chains, which constitute the peri-islet and vascular BM. We further found that the pericytic laminin isoforms differentially regulate mouse β-cells. Whereas α2 laminins promoted islet cell clustering, they did not affect gene expression. In contrast, culturing on Laminin-421 induced the expression of β-cell genes, including Ins1, MafA, and Glut2, and significantly improved glucose-stimulated insulin secretion. Thus, alongside ECs, pericytes are a significant source of the islet BM, which is essential for proper β-cell function.

Association of T-cell reactivity with β-cell function in recent onset type 1 diabetes patients

2010 ◽  
Vol 34 (2) ◽  
pp. 127-135 ◽  
Author(s):  
Christian Pfleger ◽  
Guido Meierhoff ◽  
Hubert Kolb ◽  
Nanette C. Schloot
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Function ◽  
Β Cell ◽  
Cell Reactivity ◽  
Recent Onset ◽  
Onset Type ◽  
Β Cell Function ◽  
T Cell Reactivity
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