Propargite, an environmental chemical, interacts with GWAS identified diabetes genes to impact human pancreatic β-cell death [propargite treatment]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE83699 | GEO | 2018/07/01
REPOSITORIES: GEO
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Project description:This paper describes the first time a high-content environmental chemicals screen using pancreatic β-like cells derived from human pluripotent stem cells (hPSCs), and discovered that a commonly used pesticide, propargite, induces pancreatic β-cell DNA damage and necrosis. More interestingly, we found out the genetic background of β-like cells affects their response to propargite-induced toxicity, based on isogenic hPSC platform, including for variants GWAS identified associated with T1D, since isogenic GSTT1-/- and PTPN2-/- pancreatic β-like cells are hypersensitive to propargite-induced β-cell death both in vitro and in vivo. In summary, our study identified an environmental chemical that contributes to the loss of β-cells and provides an innovative platform for using hPSC-derived cells to explore gene-environment interactions that impact diabetes disease progression.
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Project description:Over 90% of disease associated single nucleotide polymorphisms (SNPs) identified by genome wide association studies (GWAS) are noncoding variants. Platform to efficiently validate the biological function of variants thus discovered remain distinctly lacking. Here, we used β-like cells derived from isogenic human pluripotent stem cells (hPSCs), carrying the type 1 diabetes (T1D)-associated noncoding SNP rs2542151T>G or the knockout of the SNP-associated gene PTPN2−/−, to systematically examine the role of the T1D associated noncoding variant in β cell function and survival. PTPN2−/− and rs2542151T>G both decrease insulin production and elevate cell apoptosis in vitro as well as in vivo. A high content chemical screen identified sodium butyrate, a short-chain fatty acid, to rescue the defects of PTPN2−/−and rs2542151G/G β-like cells in vitro and a humanized mouse model. The combined phosphoproteomics, proteomics and RNA-seq analyses discovered a LAMIN A/HDAC/ERK/complex 1 axis as the downstream pathway of PTPN2 to control β cell survival. Together, this study proved the principle to apply hPSC-derived β cells to study diabetes associated noncoding SNP, and identified a drug candidate for the precision therapy of T1D.
2021-03-22 | GSE166785 | GEO
Project description:Protein tyrosine phosphatase N2 (Ptpn2) is a type 1 diabetes (T1D) candidate gene identified from human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation, suggesting that PTPN2 may be important for beta cell survival in the context of T1D. To test whether PTPN2 contributed to beta cell dysfunction in an inflammatory environment, we generated a beta cell-specific deletion of Ptpn2 in mice (Ptpn2 βKO). While unstressed animals exhibit normal metabolic profiles, streptozotocin (STZ) Ptpn2 βKO mice display marked increase in hyperglycemia and death due to exacerbated beta cell loss. Furthermore, cytokine treated Ptpn2 KO islets resulted in mitochondrial defects and reduced glucose-induced metabolic flux, suggesting beta cells lacking Ptpn2 are more susceptible to inflammatory stress associated with T1D due to compromised metabolic fitness.
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Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.
2016-07-12 | GSE76308 | GEO
Project description:Human pluripotent stem cells (hPSCs) have the potential to generate any human cell type, and one widely recognized goal is to make pancreatic β cells. To this end, comparisons between differentiated cell types produced in vitro and their in vivo counterparts are essential to validate hPSC-derived cells. Genome-wide transcriptional analysis of sorted insulin-expressing (INS(+)) cells derived from three independent hPSC lines, human fetal pancreata, and adult human islets points to two major conclusions: (i) Different hPSC lines produce highly similar INS(+) cells and (ii) hPSC-derived INS(+) (hPSC-INS(+)) cells more closely resemble human fetal β cells than adult β cells. This study provides a direct comparison of transcriptional programs between pure hPSC-INS(+) cells and true β cells and provides a catalog of genes whose manipulation may convert hPSC-INS(+) cells into functional β cells
2014-03-25 | GSE56130 | GEO
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 from diabetic NOD mice treated with anti-CD3 monoclonal antibody and IL-1 receptor antagonist (IL-1RA). 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 islets from mice with reversed diabetes. To address the functional role of PTPN2 in β-cells, we generated PTPN2 deficient stem cell-derived β-like and human EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates the type I and type II IFN signalling networks, and the potential progression towards autoimmunity. Moreover, we established the capacity of PTPN2 to modulate the Ca2+-dependent unfolded protein response in β-cells. Adenovirus-induced overexpression of PTPN2 decreased BiP expression and partially protected from ER-stress induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.
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Project description:In contrast to conventional human pluripotent stem cells (hPSC) that are related to post-implantation embryo stages, naïve hPSC exhibit features of pre-implantation epiblast. Naïve hPSC are established by resetting conventional hPSC, or are derived from dissociated embryo inner cell masses. Here we investigate conditions for transgene-free reprogramming of human somatic cells to naïve pluripotency. We find that RNA-mediated induction of naïve pluripotency is enhanced by Wnt inhibition. We demonstrate application to independent human fibroblast cultures and endothelial progenitor cells and show that induced naïve hPSC can be clonally expanded with a diploid karyotype. They exhibit distinctive surface marker, transcriptome, and methylome properties of naïve epiblast identity. Induced naïve hPSC lines undergo somatic lineage differentiation following formative transition. Efficient, facile, and reliable induction of transgene free naïve hPSC offers a robust platform for delineation of human reprogramming trajectories and for evaluating the attributes of isogenic naïve versus conventional hPSC.
2019-12-02 | GSE130162 | GEO
Project description:An unlimited source of functional human pancreatic β cells are in highly demand. Even with recent advances in pancreatic β-like cell differentiation from human pluripotent stem cells (hPSCs), several hurdles obviously remain and the differentiation protocols need to be further improved. Chemical strategies are particularly useful to address these challenges. Here, through chemical screening, we unexpectedly identified that BET bromodomain inhibitor I-BET151 could robustly promote the expansion of PDX1 and NKX6.1 double-positive human pancreatic progenitors (PPs). These hPSC-derived expandable pancreatic progenitors (ePPs) can proliferate extensively in a chemically defined condition with I-BET151. Even after long-term expansion, these ePPs maintain pancreatic progenitor cell status. In addition, ePPs can efficiently differentiate into pancreatic β-like cells (ePP-β cells). These ePP-β cells are functional and demonstrate glucose-stimulation insulin-secretion (GSIS) capacity. Mechanistically, I-BET151 can activate Notch signaling and promote the expression of key pancreatic progenitor-associated genes and transcriptional network. Conclusively, our studies achieve the long-term goal of robust expansion of human pancreatic progenitors and represent a significant step towards unlimited supplies of functional human pancreatic β cells that are of great interest for biomedical research and regenerative medicine.
2022-02-24 | GSE175613 | GEO
Project description:An unlimited source of functional human pancreatic β cells are in highly demand. Even with recent advances in pancreatic β-like cell differentiation from human pluripotent stem cells (hPSCs), several hurdles obviously remain and the differentiation protocols need to be further improved. Chemical strategies are particularly useful to address these challenges. Here, through chemical screening, we unexpectedly identified that BET bromodomain inhibitor I-BET151 could robustly promote the expansion of PDX1 and NKX6.1 double-positive human pancreatic progenitors (PPs). These hPSC-derived expandable pancreatic progenitors (ePPs) can proliferate extensively in a chemically defined condition with I-BET151. Even after long-term expansion, these ePPs maintain pancreatic progenitor cell status. In addition, ePPs can efficiently differentiate into pancreatic β-like cells (ePP-β cells). These ePP-β cells are functional and demonstrate glucose-stimulation insulin-secretion (GSIS) capacity. Mechanistically, I-BET151 can activate Notch signaling and promote the expression of key pancreatic progenitor-associated genes and transcriptional network. Conclusively, our studies achieve the long-term goal of robust expansion of human pancreatic progenitors and represent a significant step towards unlimited supplies of functional human pancreatic β cells that are of great interest for biomedical research and regenerative medicine.
2022-02-24 | GSE156711 | GEO
Project description:An unlimited source of functional human pancreatic β cells are in highly demand. Even with recent advances in pancreatic β-like cell differentiation from human pluripotent stem cells (hPSCs), several hurdles obviously remain and the differentiation protocols need to be further improved. Chemical strategies are particularly useful to address these challenges. Here, through chemical screening, we unexpectedly identified that BET bromodomain inhibitor I-BET151 could robustly promote the expansion of PDX1 and NKX6.1 double-positive human pancreatic progenitors (PPs). These hPSC-derived expandable pancreatic progenitors (ePPs) can proliferate extensively in a chemically defined condition with I-BET151. Even after long-term expansion, these ePPs maintain pancreatic progenitor cell status. In addition, ePPs can efficiently differentiate into pancreatic β-like cells (ePP-β cells). These ePP-β cells are functional and demonstrate glucose-stimulation insulin-secretion (GSIS) capacity. Mechanistically, I-BET151 can activate Notch signaling and promote the expression of key pancreatic progenitor-associated genes and transcriptional network. Conclusively, our studies achieve the long-term goal of robust expansion of human pancreatic progenitors and represent a significant step towards unlimited supplies of functional human pancreatic β cells that are of great interest for biomedical research and regenerative medicine.
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