Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

Gurgul-Convey, Ewa; Mehmeti, Ilir; Plötz, Thomas; Jörns, Anne; Lenzen, Sigurd

doi:10.1007/s00125-016-4060-y

Cited by 60 publications

(86 citation statements)

References 51 publications

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“…Such elegant work provides an important and promising method to safely enable the implantation of such human insulin‐releasing cell lines to enable their exploitation as an alternative to pancreatic islet transplantation. More recently, yet, cellular responses of this cell line to cytokine toxicity were observed to be similar to primary human beta‐cells . As with 1.1B4 cells, EndoC‐beta cell lines have been exploited for research in multiple areas including beta‐cell physiology and survival and the pathogenesis of diabetes, as has been recently documented in an excellent review by the creators of these cell lines .…”

Section: Human Beta‐cell Line Development and Potential For Therapeutmentioning

confidence: 88%

Cellular models for beta‐cell function and diabetes gene therapy

2018

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Diabetes is characterized by the destruction and/or relative dysfunction of insulin-secreting beta-cells in the pancreatic islets of Langerhans. Consequently, considerable effort has been made to understand the physiological processes governing insulin production and secretion in these cells and to elucidate the mechanisms involved in their deterioration in the pathogenesis of diabetes. To date, considerable research has exploited clonal beta-cell lines derived from rodent insulinomas. Such cell lines have proven to be a great asset in diabetes research, in vitro drug testing, and studies of beta-cell physiology and provide a sustainable, and in many cases, more practical alternative to the use of animals or primary tissue. However, selection of the most appropriate rodent beta cell line is often challenging and no single cell line entirely recapitulates the properties of human beta-cells. The generation of stable human beta-cell lines would provide a much more suitable model for studies of human beta-cell physiology and pathology and could potentially be used as a readily available source of implantable insulin-releasing tissue for cell-based therapies of diabetes. In this review, we discuss the history, development, functional characteristics and use of available clonal rodent beta-cell lines, as well as reflecting on recent advances in the generation of human-derived beta-cell lines, their use in research studies and their potential for cell therapy of diabetes.

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Section: Human Beta‐cell Line Development and Potential For Therapeutmentioning

confidence: 88%

Cellular models for beta‐cell function and diabetes gene therapy

2018

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“…EndoC-␤H1 cells, generated by the Ravassard group (22), were the first human ␤-cell line with good glucose responsiveness and a relatively high expression of insulin. Despite their utility as a model of ␤-cell biology, overall insulin responsiveness showed suboptimal performance and variability from one laboratory to another (6,13,20). Here we describe the formation of PIs using a coculture system of murine MS1 and the human insulin line EndoC-␤H1, which corrects some of these deficiencies.…”

Section: Discussionmentioning

confidence: 99%

Human EndoC-βH1 β-cells form pseudoislets with improved glucose sensitivity and enhanced GLP-1 signaling in the presence of islet-derived endothelial cells

Spelios

Afinowicz

Tipon

et al. 2018

American Journal of Physiology-Endocrinology and Metabolism

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Three-dimensional (3D) pseudoislets (PIs) can be used for the study of insulin-producing β-cells in free-floating islet-like structures similar to that of primary islets. Previously, we demonstrated the ability of islet-derived endothelial cells (iECs) to induce PIs using murine insulinomas, where PI formation enhanced insulin production and glucose responsiveness. In this report, we examined the ability of iECs to spontaneously induce the formation of free-floating 3D PIs using the EndoC-βH1 human β-cell line murine MS1 iEC. Within 14 days, the coculturing of both cell types produced fully humanized EndoC-βH1 PIs with little to no contaminating murine iECs. The size and shape of these PIs were similar to primary human islets. iEC-induced PIs demonstrated reduced dysregulated insulin release under low glucose levels and higher insulin secretion in response to high glucose and exendin-4 [a glucagon-like peptide-1 (GLP-1) analog] compared with monolayer cells cultured alone. Interestingly, iEC-PIs were also better at glucose sensing in the presence of extendin-4 compared with PIs generated on a low-adhesion surface plate in the absence of iECs and showed an overall improvement in cell viability. iEC-induced PIs exhibited increased expression of key genes involved in glucose transport, glucose sensing, β-cell differentiation, and insulin processing, with a concomitant decrease in glucagon mRNA expression. The enhanced responsiveness to exendin-4 was associated with increased protein expression of GLP-1 receptor and phosphokinase A. This rapid coculture system provides an unlimited number of human PIs with improved insulin secretion and GLP-1 responsiveness for the study of β-cell biology.

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“…This line represents a precious tool to study human beta cells in pathophysiological conditions [29]. As an example, EndoC-βH1 cells react to cytokine exposure in a similar manner to primary human beta cells [30]. Moreover, this cell line is suitable for drug screening [31].…”

Section: Introductionmentioning

confidence: 99%

Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

et al. 2019

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Aims/hypothesis During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment. Methods EndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity. Results EndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion. Conclusions/interpretation The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity. Data availability Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.

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Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

Cited by 60 publications

References 51 publications

Cellular models for beta‐cell function and diabetes gene therapy

Cellular models for beta‐cell function and diabetes gene therapy

Human EndoC-βH1 β-cells form pseudoislets with improved glucose sensitivity and enhanced GLP-1 signaling in the presence of islet-derived endothelial cells

Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

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