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Generation of Stem Cell-Derived β Cells from Type 1 Diabetic Patients

ABSTRACT: We recently reported the scalable in vitro production of functional stem cell-derived β cells. Here we extend this approach to generate SC-β cells from Type 1 diabetic patients (T1D), a cell type that is destroyed during disease progression and has not been possible to extensively study. These cells express β cell markers, respond to glucose both in vitro and in vivo, prevent alloxan-induced diabetes in mice, and respond to anti-diabetic drugs. Furthermore, we use an in vitro disease model to demonstrate the cells respond to different forms of β cell stress. Using these assays, we find no major differences in T1D SC-β cells compared to SC-β cells derived from non-diabetic patients (ND). These results show that T1D SC-β cells can be used for the treatment of diabetes, drug screening, and the study of β cell biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70901 | GEO | 2016/04/01

SECONDARY ACCESSION(S): PRJNA289894

REPOSITORIES: GEO

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Generation of Stem Cell-Derived Î² Cells from Type 1 Diabetic Patients

Project description:We recently reported the scalable in vitro production of functional stem cell-derived Î² cells. Here we extend this approach to generate SC-Î² cells from Type 1 diabetic patients (T1D), a cell type that is destroyed during disease progression and has not been possible to extensively study. These cells express Î² cell markers, respond to glucose both in vitro and in vivo, prevent alloxan-induced diabetes in mice, and respond to anti-diabetic drugs. Furthermore, we use an in vitro disease model to demonstrate the cells respond to different forms of Î² cell stress. Using these assays, we find no major differences in T1D SC-Î² cells compared to SC-Î² cells derived from non-diabetic patients (ND). These results show that T1D SC-Î² cells can be used for the treatment of diabetes, drug screening, and the study of Î² cell biology. Differentiated cells were sorted and processed for RNA isolation using the MARIS protocol published previously (PMID: 24516164.) Human induced pluripotent stem cell (hiPSC) line were differentiated into SC-beta cells or dysfunctional, polyhormonal cells (PH). Four biological replicates were assessed with differentiation to both SC-beta and PH cells. Those data were normalized together with and compared to existing, previously published data from Hrvatin et al. (PMID: 24516164) and Pagliuca et al. (PMID: 25303535) from human islet-derived insulin+ cells, undifferentiated HUES8 hES cells, SC-beta cells derived from HUES8 and PH cells derived from HUES8 according to previously published protocols.

2016-04-01 | E-GEOD-70901 | biostudies-arrayexpress

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

Project description:Type 1 and type 2 diabetes (T1D and T2D) share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, while beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alter the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role for beta cell fragility in genetic predisposition to diabetes.

2016-02-24 | PXD000859 | Pride

Subpopulations of mouse beta cells

Project description:Type 1 diabetes (T1D) is a chronic autoimmune disease that involves immune mediated destruction of β cells. How β cells respond to immune attack is unknown. We identified a population of β cells during the progression of T1D in non-obese diabetic (NOD) mice that survives immune attack. This population develops from normal β cells confronted with islet infiltrates. Pathways involving cell movement, growth and proliferation, immune responses, and cell death and survival are activated in these cells. There is reduced expression of β cell identity genes and diabetes antigens and increased immune inhibitory markers and stemness genes. This new subpopulation is resistant to killing when diabetes is precipitated with cyclosphosphamide. Human β cells show similar changes when cultured with immune cells. These changes may account for the chronicity of the disease and the long term survival of β cells in some patients.

2017-02-02 | GSE94382 | GEO

A discovery-based proteomics approach identifies protein disulfide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes

Project description:Background: Activation of stress pathways intrinsic to the β cell are thought to both accelerate β cell death and increase β cell immunogenicity in type 1 diabetes (T1D). However, information on the timing and scope of these responses is lacking. Methods: To identify temporal and disease-related changes in islet β cell protein expression, SWATH-MS/MS proteomics analysis was performed on islets collected longitudinally from NOD mice and NOD-SCID mice rendered diabetic through T cell adoptive transfer. Findings: In islets collected from female NOD mice at 10, 12, and 14 weeks of age, we found a time-restricted upregulation of proteins involved in the maintenance of β cell function and stress mitigation, followed by loss of expression of protective proteins that heralded diabetes onset. Pathway analysis identified EIF2 signaling and the unfolded protein response, mTOR signaling, mitochondrial function, and oxidative phosphorylation as commonly modulated pathways in both diabetic NOD mice and NOD-SCID mice rendered acutely diabetic by adoptive transfer, highlighting this core set of pathways in T1D pathogenesis. In immunofluorescence validation studies, β cell expression of protein disulfide isomerase A1 (PDIA1) and 14-3-3b were found to be increased during disease progression in NOD islets, while PDIA1 plasma levels were increased in pre-diabetic NOD mice and in the serum of children with recent-onset T1D compared to age and sex-matched non-diabetic controls. Interpretation: We identified a common and core set of modulated pathways across distinct mouse models of T1D and identified PDIA1 as a potential human biomarker of β cell stress in T1D.

2023-03-11 | PXD035504 | Pride

Protective Renalase-deficiency in beta cells shapes immune metabolism and function in autoimmune diabetes

Project description:Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic beta cells that produce insulin. The latest advances in stem cell (SC)-beta cell differentiation methods have made a cell replacement therapy for T1D feasible. However, recurring autoimmunity would rapidly destroy transplanted SC-beta cells. A promising strategy to overcome immune rejection is to genetically engineer SC-beta cells. We previously identified Renalase (Rnls) as a novel target for beta cell protection. Here we show that Rnls deletion endows beta cells with the capacity to modulate the metabolism and function of immune cells within the local graft microenvironment. We used flow cytometry and single-cell RNA sequencing to characterize beta cell graft-infiltrating immune cells in a mouse model for T1D. Loss of Rnls within transplanted beta cells affected both the composition and the transcriptional profile of infiltrating immune cells in favor of an anti-inflammatory phenotype with decreased antigen presenting capacity. We propose that changes in beta cell metabolism mediate local immune regulation and that this feature could be exploited for therapeutic goals.

2024-02-27 | GSE226361 | GEO

Differential gene expression in beta cells and non-beta cells from islets of NOD mice

Project description:Diabetes (T1D) is a disease in which the immune system destroys the insulin-producing beta cells. Recently, researchers have become interested in the role of the innate immune system in initiating this process. To further investigate this, we used RNA-seq to analyze sorted beta cells from non-diabetic and pre-diabetic female non-obese models of diabetes (NOD). These results shed light on the potential involvement of m6A mediators in the development of T1D, highlighting a promising avenue for future research.

2024-01-01 | GSE228219 | GEO

microRNAs of thymocytes and of peripheral and pancreas-infiltrating T lymphocytes

Project description:As early as one month of age, nonobese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes, which destruct insulin-producing beta cells, producing autoimmune diabetes mellitus (T1D) within eightmonths. Thus, we hypothesized that during the development of T1D, the transcriptional modulation of immune reactivity genes may occur as thymocytes mature into peripheral T lymphocytes. The transcriptome of thymocytes and peripheral CD3+ T lymphocytes from prediabetic or diabetic mice analyzed through microarray hybridizations identified the differentially expressed genes.

2012-07-31 | E-MEXP-3572 | biostudies-arrayexpress

Development of type 1 diabetes mellitus T1D in NOD mice follows transcriptional activity of thymocytes and peripheral T lymphocytes

Project description:Non-obese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes as early as 1 month of age, which destruct insulin-producing beta-cells to finally emerge autoimmune diabetes mellitus (T1D) within 8 months. In view, we hypothesized that during the development of T1D, transcriptional modulation of immune reactivity genes may occur as thymocytes mature toward peripheral T lymphocytes. Transcriptome of thymocytes and peripheral CD3+ T lymphocytes from pre-diabetic or diabetic mice analyzed through microarray hybridizations allowed observation of 3,586 differentially expressed genes. Hierarchical clustering grouped mice according to age/T1D onset and genes to their ontology. Transcriptional activity of thymocytes toward peripheral T lymphocytes unraveled sequential participation of genes involved with CD4+/CD8+ T cell differentiation (Themis), tolerance induction (Foxp3), apoptosis (Fasl) to soon after T cell activation (IL4), while the emergence of T1D coincided with the expression of cytotoxicity (Crtam) and inflammatory response genes (Tlr) by peripheral T lymphocytes.

2011-03-03 | E-MEXP-3047 | biostudies-arrayexpress

Proteome and (ox)PTP profile analysis of diabetic NOD mouse under single (anti-CD3) or combined (anti-CD3 + IL1RA) treatment

Project description:Type 1 diabetes (T1D) results from autoimmune destruction of β cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell function. Here, we assessed the global protein and individual PTP profile in the pancreas of diabetic NOD mice treated with anti-CD3 mAb and IL-1RA combination therapy. The treatment reversed hyperglycemia compared to the anti-CD3 alone control group. We observed enhanced expression of PTPN2, a T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the islets from cured mice.

2022-11-10 | PXD025394 | Pride

NOD Mouse Islet Peptide Content Identification

Project description:Beta-cells produce hybrid insulin peptides (HIPs) by linking insulin fragments to other peptides through peptide bonds. HIPs have unique amino acid sequences and are targeted by autoreactive T cells in type 1 diabetes (T1D). Individuals with recent-onset T1D have significantly higher levels of HIP-reactive T cells in their blood compared to non-diabetic control subjects. HIP-reactive T cells have also been found in the residual pancreatic islets of deceased T1D organ donors. In non-obese diabetic (NOD) mice, a major T1D animal model, several CD4 T cell clones that trigger diabetes have been shown to target HIPs. Through mass spectrometry, a subgroup of HIPs containing N-terminal amine groups of various peptides linked to aspartic acid residues of insulin C-peptide has been detected in NOD islets. Our research reveals that these HIPs form spontaneously in beta-cells via an aspartic anhydride intermediate mechanism. This process leads to the creation of a regular HIP with a standard peptide bond and a HIP-isomer (isoHIP) with an isopeptide bond linked to the carboxylic acid side-chain of the aspartic acid residue. Our mass spectrometric analyses confirmed the presence of both HIP isomers in murine islets, thereby validating the occurrence of this new reaction mechanism in beta-cells. The spontaneous formation of neoepitopes through the development of new peptide bonds within cells may contribute to the pathogenesis of T1D and other autoimmune diseases.

2023-11-16 | PXD041616 | Pride

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