Dysfunction of iPSC-derived endothelial cells in human Hutchinson-Gilford progeria syndrome
Gianfranco Matrone1,2, Rajarajan A Thandavarayan1, Brandon K Walther1
1Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute , Houston , TX , USA.
Insights
Hutchinson-Gilford progeria syndrome (HGPS) causes endothelial cell dysfunction, characterized by abnormal nuclear morphology and impaired function. Targeting these endothelial abnormalities may offer new therapeutic strategies for HGPS patients.
Area of Science:
- Cardiovascular Biology
- Cell Biology
- Genetics
Background:
- Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature aging.
- Endothelial dysfunction is a hallmark of atherosclerosis and may play a role in HGPS pathogenesis.
- Previous studies have not comprehensively evaluated endothelial cell function in HGPS.
Purpose of the Study:
- To characterize endothelial cell (EC) function in HGPS using patient-derived induced pluripotent stem cells (iPSCs).
- To investigate the impact of HGPS on EC morphology, proliferation, and function both in vitro and in vivo.
- To explore potential therapeutic avenues targeting endothelial dysfunction in HGPS.
Main Methods:
- Differentiated HGPS patient-derived iPSCs into endothelial cells (ECs).
- Assessed EC morphology, nuclear structure, proliferation, and telomere length (T/S ratio) using immunocytochemistry, FACS, and mmqPCR.
- Evaluated EC function in vitro (nitric oxide generation, network formation) and in vivo (vascular network formation in immunodeficient mice).
Main Results:
- HGPS iPSC-ECs exhibited smaller percentages, dysmorphic nuclei, increased size, reduced proliferation, and shortened telomeres.
- Impaired EC functions included reduced Dil-Ac-LDL uptake, nitric oxide generation, and in vitro network formation.
- In vivo, HGPS iPSC-ECs formed sparser vascular networks with fewer capillaries compared to controls.
Conclusions:
- iPSC-derived ECs from HGPS patients display significant cellular abnormalities and functional impairments.
- These findings highlight endothelial pathobiology as a key feature of HGPS.
- Targeting endothelial dysfunction presents a promising therapeutic strategy for HGPS.
Abstract:
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.
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