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Chromatin dynamics reveal circadian control of human in vitro islet maturation [ChIP-seq]

ABSTRACT: Stem cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human stem cells differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment, and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, stem cell-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, stem cell-derived tissues are amenable to functional improvement by circadian modulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140500 | GEO | 2019/11/16

REPOSITORIES: GEO

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Chromatin dynamics reveal circadian control of human in vitro islet maturation [WGBS]

Project description:Stem cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human stem cells differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment, and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, stem cell-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, stem cell-derived tissues are amenable to functional improvement by circadian modulation.

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Chromatin dynamics reveal circadian control of human in vitro islet maturation [RNA-seq]

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Chromatin dynamics reveal circadian control of human in vitro islet maturation [ATAC-seq]

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H3K4 trimethylation is required for postnatal pancreatic endocrine cell functional maturation

Project description:During pancreas development, endocrine progenitors differentiate into the islet-cell subtypes, which undergo further functional maturation in postnatal islet development. In islet b-cells, genes involved in glucose-stimulated insulin secretion are activated and glucose exposure increases the insulin response as b-cells mature. Here, we investigated the role of H3K4 trimethylation in endocrine cell differentiation and functional maturation by disrupting TrxG complex histone methyltransferase activity in mouse endocrine progenitors. In the embryo, genetic inactivation of TrxG component Dpy30 in NEUROG3+ cells did not affect the number of endocrine progenitors or endocrine cell differentiation. H3K4 trimethylation was progressively lost in postnatal islets and the mice displayed elevated non-fasting and fasting glycemia, as well as impaired glucose tolerance by postnatal day 24. Although postnatal endocrine cell proportions were equivalent to controls, islet RNA-sequencing revealed a downregulation of genes involved in glucose-stimulated insulin secretion and an upregulation of immature b-cell genes. Comparison of histone modification enrichment profiles in NEUROG3+ endocrine progenitors and mature islets suggested that genes downregulated by loss of H3K4 trimethylation more frequently acquire active histone modifications during maturation. Taken together, these findings suggest that H3K4 trimethylation is required for the activation of genes involved in the functional maturation of pancreatic islet endocrine cells.

2021-05-21 | GSE174751 | GEO

Insulin deficiency distorts human pancreatic endocrine cell composition during development

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Project description:Using 10x Genomics Chromium Single Cell 3’ RNAseq platform, we sequenced human stem cell derived pancreatic islet cells during different stages of development and maturation process. We optimized a protocol for pancreatic endocrine differentiation, particularly focusing on the final, extended maturation stage during which significant reorganization of the cytoarchitecture of islet-like aggregates took place correlating with a remarkable maturation of glucose-induced insulin secretion. The transcriptomic changes during the time-course were combined with detailed physiological studies including dynamic insulin secretion assays, respirometry measurements, electrophysiological profiling as well as imaging of calcium and cAMP signaling and exocytosis.

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Project description:We have developed an in vitro culture system that allows us to expand progenitor cells from human islet preparations and differentiate them into insulin-producing cells. We noticed however, that cultures from individual islet preparations had very heterogeneous outcomes, from good differentiation to almost none. We therefore speculated that our progenitor cell cultures contained different kinds of cells and that the true endocrine progenitor cells are present in the successful cultures, but not in the unsuccessful ones. To address this issue and to begin to identify markers for the true endocrine progenitor cells we compared global gene expression between a very successful culture (final insulin-expression 10% of islets) and an unsuccessful one (final insulin-expression 0%). We also included RNA from freshly isolated islets for control purposes. The cultures from donor A yielded substantial differentiation, while the cultures from donor B showed no successful differentiation.

2014-10-31 | E-MTAB-3050 | biostudies-arrayexpress

RNA Seq of IAPP expressing SC-β cells

Project description:Islet transplantation for treatment of diabetes is limited by availability of donor islets and requirements for immunosuppression. Stem cell-derived islets might circumvent these issues. SC-islets effectively control glucose metabolism post transplantation, but do not yet achieve full function in vitro with currently published differentiation protocols. We aimed to identify markers of mature subpopulations of SC-β cells by studying transcriptional changes associated with in vivo maturation of SC-β cells using RNA-seq and co-expression network analysis. The β cell-specific hormone islet amyloid polypeptide (IAPP) emerged as the top candidate to be such a marker. IAPP+ cells had more mature β cell gene expression and higher cellular insulin content than IAPP- cells in vitro. IAPP+ INS+ cells were more stable in long-term culture than IAPP- INS+ cells and retained insulin expression after transplantation into mice. Finally, we conducted a small molecule screen to identify compounds that enhance IAPP expression. Aconitine up-regulated IAPP and could help to optimize differentiation protocols.

2024-04-15 | GSE263366 | GEO

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Human Pluripotent Stem Cell-derived Islets Ameliorate Diabetes in Nonhuman Primates [human_singlecell]

Project description:Pluripotent stem cell-derived islets (hPSC-islets) are a promising cell resource for diabetes treatment. Here, we demonstrate that transplantation of pluripotent stem cell-derived islets into diabetic nonprimates effectively restored endogenous insulin secretion and improved glycemic control. Single-cell RNA sequencing analysis of S6D2 clusters confirmed the existence of the three major pancreatic endocrine cell populations (β cells, α-like cells and δ-like cells) and their proportions, which altogether accounted for 80%. Importantly, hierarchical clustering of S6D2 hCiPSC-islets, 10 wpt kidney grafts and primary islets showed that the hCiPSC differentiated pancreatic endocrine cells shared similar global gene expression profiles to their native counterparts in primary islets. Single-cell RNA sequencing analysis on PBMCs revealed the potential immune response of recipient macaque to hCiPSC-islets.

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