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Circulation. 2017 Sep 29. pii: CIRCULATIONAHA.116.026329. doi: 10.1161/CIRCULATIONAHA.116.026329. [Epub ahead of print]

Enhanced Therapeutic and Long-Term Dynamic Vascularization Effects of Human Pluripotent Stem Cell-Derived Endothelial Cells Encapsulated in a Nanomatrix Gel.

Author information

1
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA & Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
2
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA.
3
Department of Genetics, Yale University School of Medicine, New Haven, CT.
4
Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL.
5
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA & Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea yyoon5@emory.edu.

Abstract

Background -Human pluripotent stem cell (hPSC)-derived endothelial cells (ECs) have limited clinical utility due to undefined components in the differentiation system and poor cell survival in vivo Here, we aimed to develop a fully defined and clinically compatible system to differentiate hPSCs into ECs. Further, we aimed to enhance cell survival, vessel-formation, and therapeutic potential by encapsulating hPSC-ECs with a peptide amphiphile (PA) nanomatrix gel. Methods -We induced differentiation of hPSCs into the mesodermal lineage by culturing on collagen-coated plates with a GSK3β inhibitor. Next, VEGF, EGF, and bFGF were added for endothelial lineage differentiation followed by sorting for CDH5 (VE-Cadherin). We constructed an extracellular matrix-mimicking PA nanomatrix gel (PA-RGDS) by incorporating the cell adhesive ligand Arg-Gly-Asp-Ser (RGDS) and a matrix metalloproteinase-2 degradable sequence. We then evaluated whether the encapsulation of hPSC-CDH5+ cells in PA-RGDS could enhance long-term cell survival and vascular regenerative effects in a hindlimb ischemia model using Laser Doppler perfusion imaging, bioluminescence imaging, real-time RT-PCR, and histological analysis. Results -The resultant hPSC-derived CDH5+ cells (hPSC-ECs) showed highly enriched and genuine EC characteristics and pro-angiogenic activities. When injected into ischemic hindlimbs, hPSC-ECs showed better perfusion recovery and higher vessel-forming capacity compared to media-, PA-RGDS-, or HUVEC-injected groups. However, the group receiving the PA-RGDS-encapsulated hPSC-ECs showed better perfusion recovery, more robust and longer cell survival (> 10 months), and higher and prolonged angiogenic and vascular incorporation capabilities than the bare hPSC-EC-injected group. Surprisingly, the engrafted hPSC-ECs demonstrated previously unknown sustained and dynamic vessel-forming behavior: initial perivascular concentration, a guiding role for new vessel formation, and progressive incorporation into the vessels over 10 months. Conclusions -We generated highly enriched hPSC-ECs via a clinically compatible system. Further, this study demonstrated that a biocompatible PA-RGDS nanomatrix gel substantially improved long-term survival of hPSC-ECs in an ischemic environment and improved neovascularization effects of hPSC-ECs via prolonged and unique angiogenic and vessel-forming properties. This PA-RGDS-mediated transplantation of hPSC-ECs can serve as a novel platform for cell-based therapy and investigation of long-term behavior of hPSC-ECs.

KEYWORDS:

cardiovascular disease; endothelial cell differentiation; human pluripotent stem cells; ischemic vascular disease; nanomatrix gel; stem cell; stem cell therapy

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