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

 Shin-Jeong Lee  ;  Young-Doug Sohn  ;  Adinarayana Andukuri  ;  Sangsung Kim  ;  Jaemin Byun  ;  Ji Woong Han  ;  In-Hyun Park  ;  Ho-Wook Jun  ;  Young-sup Yoon 
 Circulation, Vol.136(20) : 1939-1954, 2017 
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Animals ; Cell Differentiation/physiology ; Cell- and Tissue-Based Therapy/methods ; Cells, Cultured ; Endothelial Cells/physiology ; Endothelial Cells/transplantation ; Hindlimb/blood supply ; Human Umbilical Vein Endothelial Cells/physiology ; Human Umbilical Vein Endothelial Cells/transplantation* ; Humans ; Ischemia/physiopathology ; Ischemia/therapy* ; Male ; Matrix Metalloproteinase 2/administration & dosage* ; Mice ; Mice, Nude ; Nanostructures/administration & dosage* ; Oligopeptides/administration & dosage* ; Pluripotent Stem Cells/physiology ; Pluripotent Stem Cells/transplantation* ; Random Allocation ; Treatment Outcome
endothelial cells ; pluripotent stem cells ; regeneration ; stem cells ; vascular diseases
BACKGROUND: Human pluripotent stem cell (hPSC)-derived endothelial cells (ECs) have limited clinical utility because of 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. Furthermore, 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 glycogen synthase kinase 3β inhibitor. Next, vascular endothelial growth factor, endothelial growth factor, and basic fibroblast growth factor 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 hind-limb ischemia model with laser Doppler perfusion imaging, bioluminescence imaging, real-time reverse transcription-polymerase chain reaction, and histological analysis. RESULTS: The resultant hPSC-derived CDH5+ cells (hPSC-ECs) showed highly enriched and genuine EC characteristics and proangiogenic activities. When injected into ischemic hind limbs, hPSC-ECs showed better perfusion recovery and higher vessel-forming capacity compared with media-, PA-RGDS-, or human umbilical vein EC-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. Furthermore, 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.
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1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부)
Yonsei Authors
윤영섭(Yoon, Young Sup) ; 이신정(Lee, Shin-Jeong)
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