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

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

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 PARGDS-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.

Original languageEnglish
Pages (from-to)1939-1954
Number of pages16
JournalCirculation
Volume136
Issue number20
DOIs
Publication statusPublished - 2017

Bibliographical note

Funding Information:
This work was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (Nos. HI16C2211 and HI15C2782), Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government (Nos. 2015M3A9C6031514 and 2016R1D1A1B03933154), National Institute of Diabetes and Digestive and Kidney Diseases (Nos. DP3-DK094346 and DP3-DK108245), National Heart, Lung, and Blood Institute (Nos. R01HL127759 and R01HL129511), and National Institutes of Health 1R01HL125391-01 to Drs Yoon and Jun.

Publisher Copyright:
© 2017 American Heart Association, Inc.

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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