Dataset Information

IPSC-Derived Endothelial Cells Affect Vascular Function in a Tissue-Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome.

ABSTRACT: Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder caused by a point mutation in the Lamin A gene that produces the protein progerin. Progerin toxicity leads to accelerated aging and death from cardiovascular disease. To elucidate the effects of progerin on endothelial cells, we prepared tissue-engineered blood vessels (viTEBVs) using induced pluripotent stem cell-derived smooth muscle cells (viSMCs) and endothelial cells (viECs) from HGPS patients. HGPS viECs aligned with flow but exhibited reduced flow-responsive gene expression and altered NOS3 levels. Relative to viTEBVs with healthy cells, HGPS viTEBVs showed reduced function and exhibited markers of cardiovascular disease associated with endothelium. HGPS viTEBVs exhibited a reduction in both vasoconstriction and vasodilation. Preparing viTEBVs with HGPS viECs and healthy viSMCs only reduced vasodilation. Furthermore, HGPS viECs produced VCAM1 and E-selectin protein in TEBVs with healthy or HGPS viSMCs. In summary, the viTEBV model has identified a role of the endothelium in HGPS.

SUBMITTER: Atchison L

PROVIDER: S-EPMC7013250 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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iPSC-Derived Endothelial Cells Affect Vascular Function in a Tissue-Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome.

Atchison Leigh L Abutaleb Nadia O NO Snyder-Mounts Elizabeth E Gete Yantenew Y Ladha Alim A Ribar Thomas T Cao Kan K Truskey George A GA

Stem cell reports 20200206 2

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder caused by a point mutation in the Lamin A gene that produces the protein progerin. Progerin toxicity leads to accelerated aging and death from cardiovascular disease. To elucidate the effects of progerin on endothelial cells, we prepared tissue-engineered blood vessels (viTEBVs) using induced pluripotent stem cell-derived smooth muscle cells (viSMCs) and endothelial cells (viECs) from HGPS patients. HGPS viECs aligned with flow but e ...[more]

PMID: 32032552

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Project description:Children with Hutchinson-Gilford progeria syndrome (HGPS) succumb to myocardial infarction and stroke in their teen years. Endothelial dysfunction is an early event in more common forms of atherosclerosis. Endothelial pathobiology may contribute to HGPS, but a comprehensive characterization of endothelial function in HGPS has not been performed. iPSCs derived from fibroblasts of HGPS patients or unaffected relatives were differentiated into endothelial cells (ECs). Immunofluorescent signal of the pluripotent stem cell markers SSEA4, Oct4, Sox2 and TRAI-60 was similar in HGPS or control iPSCs. Following the differentiation, FACS analysis and immunocytochemistry for CD31 and CD144 revealed a smaller percentage of ECs from HGPS iPSCs. Immunostaining for Lamin A revealed nuclear dysmorphology in HGPS iPSC-ECs. Furthermore, these cells were significantly larger and rounded, and they proliferated less, features which are typical of senescent endothelial cells. HGPS iPSC-ECs manifested less Dil-Ac-LDL uptake; less DAF-2DA staining for nitric oxide generation and formed fewer networks in matrigel in vitro. In immunodeficient mice injected with iPSC-ECs, HGPS iPSC-ECs generated a sparser vascular network compared to the control, with reduced capillary number. Telomere length (T/S ratio) of HGPS iPSC-EC was reduced as assessed by mmqPCR. iPSC-ECs derived from HGPS patients have dysmorphic appearance, abnormal nuclear morphology, shortened telomeres, reduced replicative capacity and impaired functions in vitro and in vivo. Targeting the endothelial abnormality in patients with HGPS may provide a new therapeutic avenue for the treatment of this condition. Abbreviations: HGPS: Hutchinson-Gilford progeria syndrome; ZMPSTE24: Zinc metallopeptidase STE24; FTI: Farnesyltransferase inhibitors; VSMCs: Vascular smooth muscle cells; iPSC: Induced pluripotent stem cells; EC: Endothelial cells; hTERT: Human telomerase reverse transcriptase; VEGF: vascular endothelial growth factor; DAF-FM DA: 3-Amino, 4-aminomethyl-2',7'-difluorofluorescein diacetate; BMP4: Bone Morphogenetic Protein 4; mmqPCR: mono chrome multiplex PCR; SCG: single-copy gene; CSI: Cell shape index.

Project description:PURPOSE:Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. METHODS:Children from two successive clinical trials administering 1) lonafarnib (n?=?26) and 2) lonafarnib?+?pravastatin?+?zoledronic acid (n?=?37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3?years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. RESULTS:Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p?=?0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p?=?0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p?<?0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium?×?phosphorus product (Ca?×?Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p?=?0.03). CONCLUSIONS:Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca?×?Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Dataset Information

IPSC-Derived Endothelial Cells Affect Vascular Function in a Tissue-Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome.

Publications

iPSC-Derived Endothelial Cells Affect Vascular Function in a Tissue-Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome.

Similar Datasets

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