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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

DC FieldValueLanguage
dc.contributor.author윤영섭-
dc.contributor.author이신정-
dc.date.accessioned2018-07-20T12:03:31Z-
dc.date.available2018-07-20T12:03:31Z-
dc.date.issued2017-
dc.identifier.issn0009-7322-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/161710-
dc.description.abstractBACKGROUND: 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.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherLippincott Williams & Wilkins-
dc.relation.isPartOfCirculation-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAnimals-
dc.subject.MESHCell Differentiation/physiology-
dc.subject.MESHCell- and Tissue-Based Therapy/methods-
dc.subject.MESHCells, Cultured-
dc.subject.MESHEndothelial Cells/physiology-
dc.subject.MESHEndothelial Cells/transplantation-
dc.subject.MESHHindlimb/blood supply-
dc.subject.MESHHuman Umbilical Vein Endothelial Cells/physiology-
dc.subject.MESHHuman Umbilical Vein Endothelial Cells/transplantation*-
dc.subject.MESHHumans-
dc.subject.MESHIschemia/physiopathology-
dc.subject.MESHIschemia/therapy*-
dc.subject.MESHMale-
dc.subject.MESHMatrix Metalloproteinase 2/administration & dosage*-
dc.subject.MESHMice-
dc.subject.MESHMice, Nude-
dc.subject.MESHNanostructures/administration & dosage*-
dc.subject.MESHOligopeptides/administration & dosage*-
dc.subject.MESHPluripotent Stem Cells/physiology-
dc.subject.MESHPluripotent Stem Cells/transplantation*-
dc.subject.MESHRandom Allocation-
dc.subject.MESHTreatment Outcome-
dc.titleEnhanced Therapeutic and Long-Term Dynamic Vascularization Effects of Human Pluripotent Stem Cell-Derived Endothelial Cells Encapsulated in a Nanomatrix Gel-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Life Science-
dc.contributor.googleauthorShin-Jeong Lee-
dc.contributor.googleauthorYoung-Doug Sohn-
dc.contributor.googleauthorAdinarayana Andukuri-
dc.contributor.googleauthorSangsung Kim-
dc.contributor.googleauthorJaemin Byun-
dc.contributor.googleauthorJi Woong Han-
dc.contributor.googleauthorIn-Hyun Park-
dc.contributor.googleauthorHo-Wook Jun-
dc.contributor.googleauthorYoung-sup Yoon-
dc.identifier.doi10.1161/CIRCULATIONAHA.116.026329-
dc.contributor.localIdA02579-
dc.contributor.localIdA05377-
dc.relation.journalcodeJ00533-
dc.identifier.eissn1524-4539-
dc.identifier.pmid28972000-
dc.identifier.urlhttp://circ.ahajournals.org/content/136/20/1939.long-
dc.subject.keywordendothelial cells-
dc.subject.keywordpluripotent stem cells-
dc.subject.keywordregeneration-
dc.subject.keywordstem cells-
dc.subject.keywordvascular diseases-
dc.contributor.alternativeNameYoon, Young Sup-
dc.contributor.alternativeNameLee, Shin-Jeong-
dc.contributor.affiliatedAuthorYoon, Young Sup-
dc.contributor.affiliatedAuthorLee, Shin-Jeong-
dc.citation.volume136-
dc.citation.number20-
dc.citation.startPage1939-
dc.citation.endPage1954-
dc.identifier.bibliographicCitationCirculation, Vol.136(20) : 1939-1954, 2017-
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers

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