Differential microvascular endothelial cell responses in the retina in diabetes compared to the heart and kidneys, a spatial transcriptomic analysis.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE263128 | GEO | 2024/09/30
REPOSITORIES: GEO
Similar Datasets
Project description:The mouse trachea is thought to contain two distinct stem cell compartments that contribute to airway repair—basal cells in the surface airway epithelium (SAE) and an unknown submucosal gland (SMG) cell type. Whether a lineage relationship exists between these two stem cell compartments remains unclear. Using lineage tracing of glandular myoepithelial cells (MECs), we demonstrate that MECs can give rise to seven cell types of the SAE and SMGs following severe airway injury. MECs progressively adopted a basal cell phenotype on the SAE and established lasting progenitors capable of further regeneration following reinjury. MECs activate Wnt-regulated transcription factors (Lef-1/TCF7) following injury and Lef-1 induction in cultured MECs promoted transition to a basal cell phenotype. Surprisingly, dose-dependent MEC conditional activation of Lef-1 in vivo promoted self-limited airway regeneration in the absence of injury. Thus, modulating the Lef-1 transcriptional program in MEC-derived progenitors may have regenerative medicine applications for lung diseases.
2018-04-30 | GSE111650 | GEO
Project description:Diabetes is prevalent worldwide and associated with severe health complications, including blood vessel damage that leads to cardiovascular disease and death. We report the development of 3D blood vessel organoids from human embryonic and induced pluripotent stem cells. These human blood vessel organoids contain endothelium, perivascular pericytes, and basal membranes, and self-assemble into lumenized interconnected capillary networks. We treat these vascular organoids with hyperglycemia and inflammatory cytokines in vitro, which leads to basement membrane thickening, a structural hallmark of diabetic patient. To compare differential gene expression we performed RNAseq on endothelial cells, derived from control (NG) or diabetic (DI) vascular organoids.
2018-08-01 | GSE89475 | GEO
Project description:Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cells (mEC) populations which are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4 + mECs are enriched in red oxidative muscle areas while ATF3/4 low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4 + mECs are more angiogenic when compared to white ATF3/4 low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4 + ) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.
2021-06-15 | GSE174785 | GEO
Project description:Hyperglycemia is the hallmark of diabetes mellitus that results in oxidative stress, endothelial dysfunction and vascular complications of diabetes. MicroRNAs (miRNAs) play a role in the development of endothelial dysfunction in diabetes, with potential application for the future therapy of diabetic vascular complications. However, there is a limited number of studies that characterize the miRNA profile of endothelial cells exposed to hyperglycemic condition. This study aimed to identify the miRNA profile of human umbilical vein endothelial cells (HUVEC) exposed to hyperglycemic state using RNA sequencing analysis.
2023-07-06 | GSE229207 | GEO
Project description:Hyperglycemia is a hallmark in prediabetes and type 2 diabetes mellitus (T2DM) which increases risk of micro and macrovascular complications such as diabetic retinopathy, diabetic nephropathy (microvascular complications), and peripheral vascular disease, cerebrovascular disease and cardiovascular diseases (macrovascular complications). Endothelial cells are affected in both cases. In this study, we investigated the miRNA expression changes in HUVECs during different glucose treatment (5mM, 10mM, 25mM and 40mM glucose) at various time intervals (6, 12, 24 and 48hrs). The results of miRNA microarray showed there is a correlation between hyperglycemia induced endothelial dysfunction and miRNA expression. In silico prediction showed that the following pathways: Regulation of actin cytoskeleton, PI3K-Akt signaling pathway, Apoptosis, Neurotrophin signaling pathway, and Insulin signaling pathway, were dysregulated during hyperglycemia. Majority of the pathways are related to apoptosis. 10 miRNAs (miR-26a-5p, -26b-5p, 29b-3p, 29c-3p, 125b-1-3p, -130b-3p, - 140-5p, -221-3p, -192-5p, and -320a,) showed increased expression with increasing concentration of glucose treatment. miR-26a-5p, -29b-3p, - 140-5p, -221-3p, and -192-5p are involves in endothelial apoptosis. Our study revealed miRNAs (miR-29b-3p and – 192-5p) with known mRNA targets (BCL2 and MCL1) showed expression pattern inversely correlating with their respective target mRNAs. Therefore these miRNAs could involve in the endothelial dysfunction due to hyperglycemia.
2016-05-23 | GSE74296 | GEO
Project description:Type 2 diabetes is an increasing pandemic health problem and leads to several late diabetic complications of organs including kidney and eye. Lowering elevated blood glucose levels is the typical therapeutic goal in clinical medicine. However, it is possible that hyperglycemia is only a symptom of diabetes but not the correct target to monitor, in order to prevent late diabetic complications. Instead, other diabetes-related alterations could be primary causes for late diabetic complications. Here, we studied the role of CaM Kinase II δ (CaMKIIδ) that is activated through diabetic metabolism. CaMKIIδ is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor mutant mice to mice lacking CaMKIIδ globally. Remarkably, CaMKIIδ-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we found evidence for improved insulin sensing and increased glucose transport into skeletal muscle. Despite normoglycemia CaMKIIδ-deficient diabetic mice developed the full picture of diabetic nephropathy. In contrast, diabetic retinopathy was prevented. These data challenge the clinical concept of normalizing elevated high glucose levels in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolites in different organs.
2021-09-06 | GSE157739 | GEO
Project description:The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk RNAseq of IR versus non-IR human salivary glands showed that neurotrophin signaling is highly disrupted post-radiation. Moreover, neurotrophin receptors (NTRs) are significantly upregulated in myoepithelial cells (MECs) post-IR, and scRNAseq revealed that MECs are a main source of neurotrophin ligands. Using two ex vivo models, we show that nerve growth factor (NGF) is essential for MEC differentiation during development, whereas upregulation of NTRs in adult MECs is associated with differentiation defects. The latter morphological abnormalities were confirmed in MECs of human IR glands. As MECs are required for proper acinar cell contraction and secretion, we propose that MEC-specific upregulation of NTRs post-IR disrupts MEC differentiation and potentially hinders the ability of the gland to regenerate.
2023-03-23 | GSE206878 | GEO
Project description:Patients with long-duration diabetes develop cardiovascular complications resulting in highly increased mortality and complications which affect the kidneys, eyes and peripheral nerves associated with high morbidity. Among the diabetic complications, damage in the eye, diabetic retinopathy, is the most common microvascular complication of diabetes. Diabetic retinopathy is a leading cause of vision-loss globally. It is characterized by a number of different patho-mechanisms including changes in vascular permeability, capillary degeneration, and finally at a late stage overshooting formation of new blood vessels. This expression analysis focused on the use of different experimental models for Diabetes Mellitus and its complications (for a review see 1: Al-Awar et al: Experimental Diabetes Mellitus in Different Animal Models. J Diabetes Res. 2016; doi: 10.1155/2016/9051426). By that, we wanted to uncover the relative contributions of systemic hyperinsulinaemia and/or hyperglycemia to molecular regulations. The following models have been used: As insulinopenic, hyperglycemic model reflecting Type 1 diabetes, male STZ-Wistar rats (60mg/kg BW; i.p.) were used. Wistar rats without STZ injection served as non-diabetic controls. Male obese ZDF rats (Fa/Fa) were used as type-2 diabetes model characterized by persisting hyperglycemia and transient hyperinsulinemia. Male lean ZDF rats (Fa/-) served as non-diabetic controls. Male obese ZF rats (Fa/Fa) hyperglycemia were used reflecting euglycemia and severe insulin resistance. Male lean ZF rats (Fa/-) served as controls. ZDF and ZF rats were obtained in two genotypes, obese (genotype fa/fa) and lean littermates (genotype Fa/?). All rats were housed in standard cages under a normal light-dark cycle for 16 weeks. All animals had free access to food and water. ZF and Wistar rats received a standard chow (Ssniff R/M) and ZDF rats received Purina 5008 chow. A group size of n=8 were used for all study groups. Wistar rats were rendered type-1 like hyperglycemic and hypoinsulinemic via a single injection of streptocotocin (STZ, 60mg/kg; i.p.) at 7 weeks of age. Obese ZDF rats (fa/fa) develop spontaneously a type-2 diabetes phenotype with persisting hyperglycemia and transient hyperinsulinemia (hyperglycemic, hypoinsulinemic). Obese ZF rats (fa/fa) develop insulin resistance with permanent hyperinsulinemia without concomitant hyperglycemia and no overt diabetes phenotype. Non STZ treated Wistar rats, lean ZDF littermates (Fa/?), and lean ZF littermates (Fa/?) served as controls. All groups were kept for 12 weeks on respective conditions together with appropriate age-matched controls. Unbiased gene expression analysis was performed per group using Affymetrix gene arrays.
2017-03-31 | E-MTAB-5563 | biostudies-arrayexpress
Project description:Purpose. Patients with diabetic retinopathy may experience severe vision loss due to macular edema and neovascularization secondary to vascular abnormalities. However, before these abnormalities become apparent, there are functional deficits in contrast sensitivity, color perception, and dark adaptation. The goals of this study are to evaluate early changes (up to 3 months) in retinal gene expression, selected visual cycle proteins, and optokinetic tracking (OKT) in streptozotocin (STZ)-induced diabetic rats.Methods. Retinal gene expression in diabetic Long Evans rats was measured by whole genome microarray 7 days, 4 weeks, and three months after onset of hyperglycemia. Select gene and protein changes were probed by PCR and immunohistochemistry respectively, and OKT thresholds were measured using a virtual optokinetics system. Results. Microarray analysis showed that the most consistently affected molecular and cellular functions were cell-to-cell signaling and interaction, cell death, cellular growth and proliferation, molecular transport, and cellular movement. Further analysis revealed reduced expression of several genes encoding visual cycle proteins including lecithin:retinol acyltransferase (LRAT), retinal pigment epithelium (RPE)-specific protein 65kDa (RPE65) and RPE retinal G protein coupled receptor (RGR). Immunohistochemistry revealed a decrease in RPE65 in the RPE layer of diabetic rats. These molecular changes occurred simultaneously with a decrease in OKT thresholds by 4 weeks of diabetes. Conclusions. The data presented here are further evidence that inner retinal cells are affected by hyperglycemia prior to vasculopathy suggesting that glial and neuronal dysfunction may underlie some of the early visual deficits in diabetics. At each of the three timepoints (day 7, day 28, and day 84) one retina each from three diabetic rats were pooled for analysis on a single microarray chip. Three independent experiments were conducted for each group (n=9 animals/group). Each timepoint contained a hyperglycemic (STZ) and a control (buffer injection only) group. Additionally, on day 7 gene changes in the retina of rats which received a single injection of STZ, but did not develop hyperglycemia (STZ-non-c) were analyzed.
2011-10-31 | E-GEOD-28831 | biostudies-arrayexpress
Project description:Diabetes is prevalent worldwide and associated with severe health complications, including blood vessel damage that leads to cardiovascular disease and death. Here we report the development of a 3D blood vessel organoid culture system from human pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into interconnected capillary networks enveloped by a basement membrane. Human blood vessel organoids transplanted into mice form a stable, perfused human vascular tree, including human arteries, arterioles and venules. Exposure of blood vessel organoids to hyperglycemia and inflammatory cytokines in vitro induced thickening of the basal membrane, a hallmark of human diabetic microangiopathy. Human blood vessel, exposed in vivo to a diabetic milieu in mice, also mimick the microvascular changes in diabetic patients. We finally performed a drug screen and uncovered γ-secretase and DLL4-Notch3 as key drivers of “diabetic” vasculopathy in human blood vessels in vitro and in vivo. Thus, organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable to model and identify drug targets for diabetic vasculopathy, which affects hundreds of millions of patients.
2018-10-31 | GSE117469 | GEO