Progeria-based vascular model identifies networks associated with cardiovascular aging and disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA967644 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24449500.fastq.gz | Fastqsanger.gz | |||
| SRR24449501.fastq.gz | Fastqsanger.gz | |||
| SRR24449502.fastq.gz | Fastqsanger.gz | |||
| SRR24449503.fastq.gz | Fastqsanger.gz | |||
| SRR24449504.fastq.gz | Fastqsanger.gz |
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Project description:To model Hutchinson-Gilford Progeria syndrome (HGPS), we differentiated patient-derived induced pluripotent stem cells (iPSCs) to vascular smooth muscle cells (VSMCs). We then performed gene expression profiling analysis using data obtained from RNA-seq of the serially passaged cells at passage7 and passage 14.
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Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature aging disease1-5, characterized by premature atherosclerosis and degeneration of vascular smooth muscle cells (SMCs)6-8. HGPS is caused by a single-point mutation in the LMNA gene, resulting in the generation of progerin, a truncated mutant of lamin A. Accumulation of progerin leads to various aging-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9-12. Here, we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS-iPSCs, progerin and its associated aging consequences are restored. In particular, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescent SMC phenotypes associated with vascular aging. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a component of the progerin-containing protein complex. The absence of nuclear DNAPKcs correlates with premature as well as physiological aging. Since progerin also accumulates during physiological aging6,12,13, our results provide an in vitro iPSC-based model with an acceleration progerin accumulation to study the pathogenesis of human premature and physiological vascular aging. Microarray gene expression profiling was done to: (1) Compare differences between WT fibroblasts and fibroblasts from patients suffering of the Hutchinson-Gilford progeria syndrome (2) Check that iPSC originating from WT and patients are in fact similar to ESC
2011-03-14 | E-GEOD-24487 | biostudies-arrayexpress
Project description:Our goal was to identify gene expression and functional differences between directly reprogrammed vascular cells derived from young and old individuals, as wells as from healthy and Hutchinson-Gilford Progeria Syndrome (HGPS) donors. We provided a full characterization of reprogrammed endothelial and smooth muscle cells by comparing their gene expression with both the original fibroblasts and primary vascular cells, showing that reprogrammed cells express key vascular cell-identity genes and contribute to the formation of in vitro 3D vascular structures. We identified and validated biomarkers of vascular dysfunction in the context of physiological and accelerated aging typical of HGPS patients, and we demonstrated their direct contribution in the modulation of vascular permeability.
2020-09-03 | GSE140898 | GEO
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature aging disease1-5, characterized by premature atherosclerosis and degeneration of vascular smooth muscle cells (SMCs)6-8. HGPS is caused by a single-point mutation in the LMNA gene, resulting in the generation of progerin, a truncated mutant of lamin A. Accumulation of progerin leads to various aging-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9-12. Here, we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS-iPSCs, progerin and its associated aging consequences are restored. In particular, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescent SMC phenotypes associated with vascular aging. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a component of the progerin-containing protein complex. The absence of nuclear DNAPKcs correlates with premature as well as physiological aging. Since progerin also accumulates during physiological aging6,12,13, our results provide an in vitro iPSC-based model with an acceleration progerin accumulation to study the pathogenesis of human premature and physiological vascular aging.
2011-03-14 | GSE24487 | GEO
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that causes accelerated aging and a high risk of cardiovascular complications. However, the underlying mechanisms of cardiac complications of this syndrome are not fully understood. This study modeled HGPS using cardiomyocytes (CM) derived from induced pluripotent stem cells (iPSC) derived from a patient with HGPS and characterized the biophysical, morphological, and molecular changes found in these CM compared to CM derived from a healthy donor. Electrophysiological recordings revealed that the HGPS CM was functional and had normal electrophysiological properties. Electron tomography showed nuclear morphology alteration and 3D reconstruction of electron tomography images indicated structural abnormalities in HGPS CM mitochondria. High-resolution respirometry with isolated CM derived from three distinct cellular differentiations suggests that HGPS-CM had a tendency of lower oxygen consumption capacity. However, there was no difference in mitochondrial content as measured by Mitotracker. Telomere length was measured using qRT-PCR, and no difference was found in either the iPSCs or the CM from HGPS when compared to the control. Proteomic analysis was carried out in a high-resolution system using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). The proteomics data show distinct group separations and protein expression differences between HGPS and control-CM, highlighting changes in ribosomal, TCA cycle, and amino acid biosynthesis, among other modifications. Our findings show that iPSC-derived cardiomyocytes from a Progeria Syndrome patient have significant changes in mitochondrial morphology and protein expression, implying novel mechanisms underlying premature cardiac aging
2022-11-10 | PXD036557 | Pride
Project description:Direct reprogramming of fibroblasts identifies signatures of vascular dysfunction in physiological aging and Hutchinson-Gilford Progeria Syndrome
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Project description:Hematopoiesis advances cardiovascular disease by generating inflammatory leukocytes that attack the arteries, heart and brain. While it is well documented that the bone marrow niche regulates hematopoietic stem cell proliferation and hence the systemic leukocyte pool, it is less clear how cardiovascular disease affects the vasculature forming this niche. Here we show that arterial hypertension, atherosclerosis and myocardial infarction alter the anatomy and function of bone marrow vasculature. Hypertension and atherosclerosis instigated vascular fibrosis, leakage and endothelial dysfunction in the bone marrow. Myocardial infarction induced vascular leakage and bone marrow angiogenesis via Vegf signaling. Endothelial cell-specific deletion of the Vegf receptor 2 limited emergency hematopoiesis after myocardial infarction, indicating that new vasculature supports higher blood cell production. RNA-sequencing of bone marrow endothelial cells revealed inflammatory gene expression in mice with cardiovascular disease. Endothelial cell-specific deletion of interleukin 6 or versican, which were highly expressed in mice with atherosclerosis or myocardial infarction, respectively, reduced hematopoiesis and systemic myeloid cells. Taken together, cardiovascular disease affects the vascular bone marrow niche, thus influencing hematopoietic stem cell behavior and expanding innate immune cell supply to atherosclerotic plaque and ischemic myocardium. Interrupting this feed back loop may constrain cardiovascular inflammation.
2021-09-27 | GSE144498 | GEO
Project description:Endothelial defects significantly contribute to cardiovascular pathology in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Using an endothelium-specific progeria mouse model, we identify a novel, endothelium-specific microRNA (miR) signature linked to the p53-senescence pathway and a senescence-associated secretory phenotype (SASP). Progerin-expressing endothelial cells exert profound cell-non-autonomous effects initiating senescence in non-endothelial cell populations and causing immune cell infiltrates around blood vessels. Comparative miR expression analyses revealed unique upregulation of senescence-associated miR34a-5p in endothelial cells with strong accumulation at atheroprone aortic arch regions but also, in whole cardiac- and lung tissues as well as in the circulation of progeria mice. Mechanistically, miR34a-5p knockdown reduced not only p53 levels but also late-stage senescence regulator p16 with no effect on p21 levels, while p53 knockdown reduced miR34a-5p and partially rescued p21-mediated cell cycle inhibition with a moderate effect on SASP. These data demonstrate that miR34a-5p reinforces two separate senescence regulating branches in progerin-expressing endothelial cells, the p53- and p16-associated pathways, which synergistically maintain a senescence phenotype that contributes to cardiovascular pathology. Thus, the key function of circulatory miR34a-5p in endothelial dysfunction-linked cardiovascular pathology offers novel routes for diagnosis, prognosis and treatment for cardiovascular aging in HGPS and potentially geriatric patients. This research was supported by by the Austrian Science Fund grant [P 32595 /Grant DOI: 10.55776/P32595] to Selma Osmanagic-Myers, and (I 4694-B) to Roland Foisner, the latter under the frame of EJP RD, the European Joint Programme on Rare Diseases. In addition, this project has received funding from the European Union’s Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP N 825575. https://www.doi.org/10.55776/P32595
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