Dataset Information

Macroencapsulated Human iPSC-Derived Pancreatic Progenitors Protect against STZ-Induced Hyperglycemia in Mice.

ABSTRACT: In type 1 diabetes, a renewable source of human pancreatic ? cells, in particular from human induced pluripotent stem cell (hiPSC) origin, would greatly benefit cell therapy. Earlier work showed that pancreatic progenitors differentiated from human embryonic stem cells in vitro can further mature to become glucose responsive following macroencapsulation and transplantation in mice. Here we took a similar approach optimizing the generation of pancreatic progenitors from hiPSCs. This work demonstrates that hiPSCs differentiated to pancreatic endoderm in vitro can be efficiently and robustly generated under large-scale conditions. The hiPSC-derived pancreatic endoderm cells (HiPECs) can further differentiate into glucose-responsive islet-like cells following macroencapsulation and in vivo implantation. The HiPECs can protect mice from streptozotocin-induced hyperglycemia and maintain normal glucose homeostasis and equilibrated plasma glucose concentrations at levels similar to the human set point. These results further validate the potential use of hiPSC-derived islet cells for application in clinical settings.

SUBMITTER: Haller C

PROVIDER: S-EPMC6449839 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Macroencapsulated Human iPSC-Derived Pancreatic Progenitors Protect against STZ-Induced Hyperglycemia in Mice.

Haller Corinne C Piccand Julie J De Franceschi Filippo F Ohi Yuki Y Bhoumik Anindita A Boss Christophe C De Marchi Umberto U Jacot Guillaume G Metairon Sylviane S Descombes Patrick P Wiederkehr Andreas A Palini Alessio A Bouche Nicolas N Steiner Pascal P Kelly Olivia G OG R-C Kraus Marine M

Stem cell reports 20190307 4

In type 1 diabetes, a renewable source of human pancreatic β cells, in particular from human induced pluripotent stem cell (hiPSC) origin, would greatly benefit cell therapy. Earlier work showed that pancreatic progenitors differentiated from human embryonic stem cells in vitro can further mature to become glucose responsive following macroencapsulation and transplantation in mice. Here we took a similar approach optimizing the generation of pancreatic progenitors from hiPSCs. This work demonstr ...[more]

PMID: 30853374

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Project description:The current study was performed to investigate the effects and potential effects of irbesartan pretreatment on pancreatic ?-cell apoptosis in a streptozotocin- (STZ-) induced acute mouse model of prediabetes. Twenty-four male BALB/C mice (18-22?g) were randomly divided into three groups: normal control group (NC, n = 6), STZ group (STZ, n = 8), and irbesartan?+?STZ group (IRB?+?STZ, n = 10). In the IRB?+?STZ group, mice were administered irbesartan (300?mg/kg per day) by gavage for one week. The STZ group and IRB?+?STZ group received STZ (80?mg/kg by intraperitoneal (IP) injection once). The NC group received normal saline (80?mg/kg by IP injection once). Fasting blood glucose prior to STZ injection and presacrifice was analysed using samples withdrawn from the caudal vein to confirm the induction of prediabetes. Haematoxylin and eosin staining, immunohistochemical detection of insulin, and apoptosis analysis were performed. Reverse transcription-quantitative polymerase chain reaction was used to detect angiotensin II type 1 receptor (AT1R), caspase-3, and p38 mitogen-activated protein kinase (MAPK) mRNA expression. Blood glucose was significantly higher in the STZ group (9.01?±?1.1089 vs 4.78?±?0.7026) and IRB?+?STZ group (7.86?±?1.1811 vs 4.78?±?0.7026) compared with the NC group (P < 0.05). In comparison to the STZ group, the islet cell damage was marginally improved in the IRB?+?STZ group, and the IRB?+?STZ group had a significantly lower apoptotic rate than the STZ group (22.42?±?8.3675 vs 50.86?±?5.3395, P < 0.001). AT1R expression in the IRB?+?STZ group was lower than that in the STZ group (1.56?±?1.2207 vs 3.92?±?2.4392, P < 0.05). The mRNA expression of caspase-3 in pancreatic tissue was significantly lower in the IRB?+?STZ group than in the STZ group (0.90?±?0.7272 vs 1.88?±?1.0572, P < 0.05). Similarly, the IRB?+?STZ group also had lower p38MAPK levels than the STZ group (1.16?±?1.0642 vs 2.55?±?1.7925, P > 0.05). In conclusion, irbesartan pretreatment improved glucose levels and insulin secretion and decreased islet ?-cell apoptosis to protect islet ? cells in an STZ-induced acute prediabetic mouse model.

Project description:BACKGROUND:Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages. METHODS:To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development. RESULTS:We provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. Significant changes are associated with the GO enrichment analysis in biological processes cell-cell adhesion, actin cytoskeleton organization, neuronal stem cell population maintenance, and pituitary gland development, next to protein changes previously associated with RTT, i.e., dendrite morphology and synaptic deficits. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes, and calcium signaling were affected throughout all stages analyzed. LIMITATIONS:The limitation of our study is the number of RTT patients analyzed. As the aim of our study was to investigate a large number of proteins, only one patient was considered, of which 3 different RTT iPSC clones and 3 isogenic control iPSC clones were included. Even though this approach allowed the study of mutation-induced alterations due to the usage of isogenic controls, results should be validated on different RTT patients to suggest common disease mechanisms. CONCLUSIONS:During early neuronal differentiation, there are consistent and time-point specific proteomic alterations in RTT patient cells carrying exons 3-4 deletion in MECP2. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Our results provide a valuable resource of proteins and pathways for follow-up studies, investigating common mechanisms involved during early disease stages of RTT syndrome.

Dataset Information

Macroencapsulated Human iPSC-Derived Pancreatic Progenitors Protect against STZ-Induced Hyperglycemia in Mice.

Publications

Macroencapsulated Human iPSC-Derived Pancreatic Progenitors Protect against STZ-Induced Hyperglycemia in Mice.

Similar Datasets

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