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Biomaterials. 2017 Dec;147:116-132. doi: 10.1016/j.biomaterials.2017.09.019. Epub 2017 Sep 19.

Vascular smooth muscle cells derived from inbred swine induced pluripotent stem cells for vascular tissue engineering.

Author information

1
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA.
2
Department of Surgery, Yale University, New Haven, CT 06520, USA.
3
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Anesthesiology, Yale University, New Haven, CT 06519, USA.
4
Department of Biomedical Engineering, Yale University, New Haven, CT 06519, USA.
5
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA; Department of Cardiology, Bethune First Hospital of Jilin University, ChangChun, 130021, China.
6
Department of Surgery, Yale University, New Haven, CT 06520, USA; Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, 110122, China.
7
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine Yale School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06519, USA.
8
Department of Genetics, Yale University, New Haven, CT 06519, USA.
9
Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA.
10
Department of Surgery, Yale University, New Haven, CT 06520, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
11
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale University, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
12
Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA 01605, USA.
13
Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA 02129, USA.
14
Yale Stem Cell Center, New Haven, CT 06520, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Anesthesiology, Yale University, New Haven, CT 06519, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06519, USA.
15
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine Yale School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, New Haven, CT 06520, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: yibing.qyang@yale.edu.

Abstract

Development of autologous tissue-engineered vascular constructs using vascular smooth muscle cells (VSMCs) derived from human induced pluripotent stem cells (iPSCs) holds great potential in treating patients with vascular disease. However, preclinical, large animal iPSC-based cellular and tissue models are required to evaluate safety and efficacy prior to clinical application. Herein, swine iPSC (siPSC) lines were established by introducing doxycycline-inducible reprogramming factors into fetal fibroblasts from a line of inbred Massachusetts General Hospital miniature swine that accept tissue and organ transplants without immunosuppression within the line. Highly enriched, functional VSMCs were derived from siPSCs based on addition of ascorbic acid and inactivation of reprogramming factor via doxycycline withdrawal. Moreover, siPSC-VSMCs seeded onto biodegradable polyglycolic acid (PGA) scaffolds readily formed vascular tissues, which were implanted subcutaneously into immunodeficient mice and showed further maturation revealed by expression of the mature VSMC marker, smooth muscle myosin heavy chain. Finally, using a robust cellular self-assembly approach, we developed 3D scaffold-free tissue rings from siPSC-VSMCs that showed comparable mechanical properties and contractile function to those developed from swine primary VSMCs. These engineered vascular constructs, prepared from doxycycline-inducible inbred siPSCs, offer new opportunities for preclinical investigation of autologous human iPSC-based vascular tissues for patient treatment.

KEYWORDS:

Inbred swine; Induced pluripotent stem cell; Smooth muscle cell; Tissue engineering; Vascular tissue

PMID:
28942128
PMCID:
PMC5638652
[Available on 2018-12-01]
DOI:
10.1016/j.biomaterials.2017.09.019
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