Single cell transcriptomics of human islet ontogeny defines the molecular basis of beta cell dedifferentiation in T2D
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ABSTRACT:
PROVIDER: PRJNA666806 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12756500.fastq.gz | Fastqsanger.gz | |||
| SRR12756600.fastq.gz | Fastqsanger.gz | |||
| SRR12756700.fastq.gz | Fastqsanger.gz | |||
| SRR12756800.fastq.gz | Fastqsanger.gz | |||
| SRR12756900.fastq.gz | Fastqsanger.gz |
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Project description:Dedifferentiation of pancreatic beta cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown. We employed single-cell RNAseq to detail the maturation program of alpha and beta cells during human ontogeny. We show that although both alpha and beta cells mature in part by repressing non-endocrine genes, alpha-cells retain hallmarks of an immature state, while beta-cells attain a full beta-cell specific gene expression program. In islets from T2D donors, both alpha- and beta-cells return to a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes while increasing expression of exocytosis, inflammation and stress response signaling pathways. These changes support the increased proportion of beta-cells displaying suboptimal function observed in T2D islets. These findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics.
2020-10-01 | GSE154126 | GEO
Project description:ObjectiveDedifferentiation of pancreatic β-cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown.MethodsWe employed single-cell RNAseq to detail the maturation program of α- and β-cells during human ontogeny. We also compared islets from non-diabetic and T2D individuals.ResultsBoth α- and β-cells mature in part by repressing non-endocrine genes; however, α-cells retain hallmarks of an immature state, while β-cells attain a full β-cell specific gene expression program. In islets from T2D donors, both α- and β-cells have a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes and increasing expression of exocytosis, inflammation and stress response signalling pathways. These changes are consistent with the increased proportion of β-cells displaying suboptimal function observed in T2D islets.ConclusionsThese findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics.
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Project description:Type 2 diabetes is associated with defective insulin secretion and reduced β-cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of b-cell failure is a key translational question. Here, we reverse-engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic-inflexibility and endocrine-progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca++ flux analyses of top candidate MR in islet cells validated transcription factor BACH2 and associated epigenetic effectors as a key driver of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a non-diabetic phenotype. BACH2-immunoreactive islet cells increased ~4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing b-cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
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Project description:Islets in Type 2 diabetes (T2D) share many diverse abnormalities reported in neurodegenerative diseases, including the formation of toxic oligomers from amyloidogenic proteins. We evaluated the transcriptome of murine islets with beta cell-specific human IAPP (hIAPP) expression to assess the potential contribution of hIAPP toxicity to those observed in islets from T2D.Beta cell hIAPPtoxicity induced an islet transcriptome highly analogous to that in islets from humans with T2D with a prominent inflammatory signature, activation of vascular epithelium and stellate cells, cytoskeleton remodeling,and activation of cell-cycle andcellular dedifferentiation. In conclusion, many of the apparently widely disparate changes in islets in T2D may be initiated by toxic oligomers. Inhibition of expression of amyloidogenic proteins or proximal adverse consequences such as disruption of the cytoskeleton by calpain hyperactivation are rational targets for therapeutic intervention in T2D and neurodegenerative disease.
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Project description:Blood glucose levels are tightly controlled by the coordinated action of at least five cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 diabetes (T2D). Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet dysfunction, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single cell transcriptomes for 617 islet cells after profiling ~1000 cells from non-diabetic (ND) and T2D human organ donors. Analyses of non-diabetic single cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell type-specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis. Grant ID: Award No. W81XWH-16-1-0130 Grant title: Peer Reviewed Medical Research Program Funding Source: Assistant Secretary of Defense for Health Affairs Affiliation: Jackson Laboratory for Genomic Medicine, Farmington, CT Name: Michael Stitzel
2016-11-09 | GSE86468 | GEO
Project description:Blood glucose levels are tightly controlled by the coordinated action of at least five cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 diabetes (T2D). Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet dysfunction, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single cell transcriptomes for 617 islet cells after profiling ~1000 cells from non-diabetic (ND) and T2D human organ donors. Analyses of non-diabetic single cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell type-specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis. Grant ID: Award No. W81XWH-16-1-0130 Grant title: Peer Reviewed Medical Research Program Funding Source: Assistant Secretary of Defense for Health Affairs Affiliation: Jackson Laboratory for Genomic Medicine, Farmington, CT Name: Michael Stitzel
2016-11-09 | GSE86469 | GEO
Project description:Inflammation is a key component of the pathogenesis of obesity-associated type 2 diabetes (T2D). However, the nature of T2D-associated islet inflammation and its impacts on T2D-associated beta cell abnormalities remain poorly defined. Using both diet-induced and genetically modified T2D animal models, we explore immune components of islet inflammation and define their roles in regulating beta cell function and proliferation. Our studies show that T2D-associated islet inflammation is uniquely dominated by macrophages, without the involvement of adaptive immune cells. We identify two islet macrophage populations, characterized by their distinct phenotypes, anatomical distributions and functional properties. Obesity induces a local expansion of intra-islet macrophages, independent of the replenishment from circulating monocytes. In contrast, the abundance of peri-islet macrophages is negligibly affected by obesity. Functionally, intra-islet macrophages impair beta cell function in a cell-cell contact dependent manner. In contrast, both intra- and peri-islet macrophage populations are able to promote beta cell proliferation. Together, these data provide a definitive view of the genesis of T2D-associated islet inflammation and define specific roles of islet macrophages in regulating beta cell function and proliferation.
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Project description:Type-2 diabetes (T2D) mellitus results from a complex interplay of genetic and environmental factors leading to deficient insulin secretion from pancreatic islet beta cells. Here, we provide a the first comprehensive study of the human islet state of metabolically profiled pancreatectomized living human donors in relationship to glycemic control integrating clinical traits with multiple in situ islet and pre-operative blood omics datasets across the glycemia continuum from non diabetic healthy to overt T2D levels. Our transcriptomics and proteomics data suggest that progressive dysregulation of islet gene expression associated with increasing glucose intolerance is a disharmonic process resembling a non-linear trajectory of mature beta cell states towards trans-differentiation. Furthermore, we identify a unique islet gene set altered already in early-onset glucose intolerance and that, which correlates well across HbA1c levels - the gold-standard in clinical monitoring. Our findings reach beyond conventional clinical thresholds and can serve as direct or indirect prognostic markers for beta cell failure.
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