Tissue-Engineered Vascular Rings from Human iPSC-Derived Smooth Muscle Cells

Abstract

SummaryThere is an urgent need for an efficient approach to obtain a large-scale and renewable source of functional human vascular smooth muscle cells (VSMCs) to establish robust, patient-specific tissue model systems for studying the pathogenesis of vascular disease, and for developing novel therapeutic interventions. Here, we have derived a large quantity of highly enriched functional VSMCs from human induced pluripotent stem cells (hiPSC-VSMCs). Furthermore, we have engineered 3D tissue rings from hiPSC-VSMCs using a facile one-step cellular self-assembly approach. The tissue rings are mechanically robust and can be used for vascular tissue engineering and disease modeling of supravalvular aortic stenosis syndrome. Our method may serve as a model system, extendable to study other vascular proliferative diseases for drug screening. Thus, this report describes an exciting platform technology with broad utility for manufacturing cell-based tissues and materials for various biomedical applications.

Implantable tissue-engineered blood vessels from human induced pluripotent stem cells

“…Modifications of a prior EB approach were made [14], including generation of EBs from 80% confluent feeder-free hiPSC culture, and culturing EBs in mTeSR-containing medium for the first two days of growth. The hiPSC-derived VSMCs grown on matrigel-coated plates in SmGM-2 growth medium were early stage VSMCs (hiPSC-VSMCs) (Fig.…”

“…The hiPSC line (Y6) was generated from human neonatal fibroblast cells isolated from a healthy female donor using SeV particles that encode OCT3/4, KLF4, SOX2, and c-MYC genes as previously described [14]. Y6 hiPSCs were differentiated to VSMCs via an EB approach as previously described [14].…”

“…Y6 hiPSCs were differentiated to VSMCs via an EB approach as previously described [14]. Briefly, hiPSCs were cultured in mTeSR™1 self-renewal medium (STEMCELL Technologies) under feeder-free conditions until 80% confluency.…”

“…But for applications in tissue engineering, one of the challenges is to scale up the differentiation capacity to generate very large number of VSMCs. We have established a robust system to obtain over 40 million VSMCs from a single 6-well plate of feeder-free hiPSCs [14]. In this study, we hypothesize that hiPSC-VSMCs are able to generate strong and functional arterial grafts for implantation.…”

Differentiation and Application of Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells

“…87 Similarly, when hiPSCderived VSMCs were seeded onto ring-shaped agarose gels to form 3D tissue rings, the SVAS patient-derived rings exhibited higher cellular proliferation, decreased actin bundle filament formation, and an overall drop in contractile force. 88 Fibroblastderived iPSCs, taken from patients with Williams-Beuren syndrome, a disease characterized by SVAS, were also induced toward a VSMC phenotype. These showed similar behavioral properties to the SVAS-iPSC-VSMCs patients compared with healthy controls, providing clear evidence that alternative somatic cell sources can be used to generate iPSCs-VSMCs for modeling vascular diseases caused by genetic defects.…”