A Tissue Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome Using Human iPSC-derived Smooth Muscle Cells

Leigh Atchison,George A Truskey,Haoyue Zhang,Kan Cao

doi:10.1038/s41598-017-08632-4

Leigh Atchison, George A Truskey + Show 2 more

Open Access

https://doi.org/10.1038/s41598-017-08632-4

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Abstract

Hutchison-Gilford Progeria Syndrome (HGPS) is a rare, accelerated aging disorder caused by nuclear accumulation of progerin, an altered form of the Lamin A gene. The primary cause of death is cardiovascular disease at about 14 years. Loss and dysfunction of smooth muscle cells (SMCs) in the vasculature may cause defects associated with HGPS. Due to limitations of 2D cell culture and mouse models, there is a need to develop improved models to discover novel therapeutics. To address this need, we produced a functional three-dimensional model of HGPS that replicates an arteriole-scale tissue engineered blood vessel (TEBV) using induced pluripotent stem cell (iPSC)-derived SMCs from an HGPS patient. To isolate the effect of the HGPS iSMCs, the endothelial layer consisted of human cord blood-derived endothelial progenitor cells (hCB-EPCs) from a separate, healthy donor. TEBVs fabricated from HGPS iSMCs and hCB-EPCs show reduced vasoactivity, increased medial wall thickness, increased calcification and apoptosis relative to TEBVs fabricated from normal iSMCs or primary MSCs. Additionally, treatment of HGPS TEBVs with the proposed therapeutic Everolimus, increases HGPS TEBV vasoactivity and increases iSMC differentiation in the TEBVs. These results show the ability of this iPSC-derived TEBV to reproduce key features of HGPS and respond to drugs.

Highlights

A factor limiting advances in the field is that Hutchison-Gilford Progeria Syndrome (HGPS) disease progression and drug effects are primarily studied in 2D cell cultures or rodent models due to the limited number of autopsy specimens and human patients available[11,12,13]
In order to establish the utility of using smooth muscle cells (SMCs) derived from induced pluripotent stem cell (iPSC), we first investigated the function of tissue engineered blood vessel (TEBV) fabricated from iSMCs in our in vitro perfusion system as previously described[20]
TEBVs were fabricated with either human mesenchymal stem cells (MSCs), normal iSMCs, or HGPS iSMCs in the medial wall and seeded with hCB-endothelial cells (ECs) in the lumen[20]. These human cord-blood endothelial progenitor cells (hCB-ECs) function the same as vessel wall derived ECs, allowing us to isolate and identify effects induced by HGPS-derived SMCs in TEBVs22

Summary

Introduction

A factor limiting advances in the field is that HGPS disease progression and drug effects are primarily studied in 2D cell cultures or rodent models due to the limited number of autopsy specimens and human patients available[11,12,13]. Current efforts to fabricate 3D vascular constructs to study various cardiovascular diseases have focused on deriving large numbers of the two main cell types responsible for vessel function, SMCs and endothelial cells (ECs), both of which are involved in many vascular diseases. Many of these studies have used animal cells due to the difficulty in obtaining human sources as well as to avoid the need for immunosuppression in immunocompetent animal models[17]. By validating a TEBV disease model of HGPS using iPS-derived cell sources, a variety of rare genetic disorders associated with the cardiovascular system can be studied This model provides a better in vitro platform for comparing normal human cardiovascular aging and HGPS for future therapeutic discoveries. We can ameliorate the reduced vasoactivity seen in HGPS iSMC TEBVs through short term treatment with the rapamycin analog, RAD001 (Everolimus)

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