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

SUMMARYHutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently believed to stem primarily from heart failure secondary to central arterial stiffening. We analyze novel longitudinal cardiovascular data from a mouse model of HGPS (LmnaG609G/G609G) using allometric scaling and advanced computational modelling and show that a late-stage increase in pulse wave velocity, with associated diastolic dysfunction but preserved systolic function, emerges with a loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the entire aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, vascular function appears to be normal within the low stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last quarter of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.DisclosuresD.T.B is an equity holder in, and receives research and consulting support from, Inozyme Pharma, Inc. for therapeutics for ENPP1 deficiency. None of the other authors declare any conflict, financial or otherwise.

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Decision letter: Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and Hutchinson-Gilford progeria syndrome

10.7554/elife.54383.sa1 ◽

2020 ◽

Author(s):

Andrew S Yoo

Keyword(s):

Endothelial Cells ◽

Smooth Muscle ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Direct Reprogramming ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and Hutchinson-Gilford progeria syndrome

eLife ◽

10.7554/elife.54383 ◽

2020 ◽

Vol 9 ◽

Author(s):

Simone Bersini ◽

Roberta Schulte ◽

Ling Huang ◽

Hannah Tsai ◽

Martin W Hetzer

Keyword(s):

Endothelial Cells ◽

Smooth Muscle ◽

Vascular Endothelial Cells ◽

Functional Assay ◽

Vascular Endothelial ◽

Vascular Aging ◽

Direct Reprogramming ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Vascular dysfunctions are a common feature of multiple age-related diseases. However, modeling healthy and pathological aging of the human vasculature represents an unresolved experimental challenge. Here, we generated induced vascular endothelial cells (iVECs) and smooth muscle cells (iSMCs) by direct reprogramming of healthy human fibroblasts from donors of different ages and Hutchinson-Gilford Progeria Syndrome (HGPS) patients. iVECs induced from old donors revealed upregulation of GSTM1 and PALD1, genes linked to oxidative stress, inflammation and endothelial junction stability, as vascular aging markers. A functional assay performed on PALD1 KD VECs demonstrated a recovery in vascular permeability. We found that iSMCs from HGPS donors overexpressed bone morphogenetic protein (BMP)−4, which plays a key role in both vascular calcification and endothelial barrier damage observed in HGPS. Strikingly, BMP4 concentrations are higher in serum from HGPS vs. age-matched mice. Furthermore, targeting BMP4 with blocking antibody recovered the functionality of the vascular barrier in vitro, hence representing a potential future therapeutic strategy to limit cardiovascular dysfunction in HGPS. These results show that iVECs and iSMCs retain disease-related signatures, allowing modeling of vascular aging and HGPS in vitro.

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Paradoxical aortic stiffening and subsequent cardiac dysfunction in Hutchinson–Gilford progeria syndrome

Journal of The Royal Society Interface ◽

10.1098/rsif.2020.0066 ◽

2020 ◽

Vol 17 (166) ◽

pp. 20200066

Author(s):

S.-I. Murtada ◽

Y. Kawamura ◽

A. W. Caulk ◽

H. Ahmadzadeh ◽

N. Mikush ◽

...

Keyword(s):

Late Stage ◽

Vascular Function ◽

Systolic Function ◽

Computational Modelling ◽

Early Death ◽

Therapeutic Window ◽

Lamin A ◽

Material Stiffness ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently thought to stem primarily from cardiovascular events. We analyse novel longitudinal cardiovascular data from a mouse model of HGPS ( Lmna G609G/G609G ) using allometric scaling, biomechanical phenotyping, and advanced computational modelling and show that late-stage diastolic dysfunction, with preserved systolic function, emerges with an increase in the pulse wave velocity and an associated loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and a marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, the vascular function appears to arise normally from the low-stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last third of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.

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