A comparison of the pro-angiogenic potential of human induced pluripotent stem cell derived endothelial cells and induced endothelial cells in a murine model of peripheral arterial disease

Zoe E. Clayton, Gloria S.C. Yuen, Sara Sadeghipour, Jack D. Hywood, Jack W.T. Wong, Ngan F. Huang, Martin K.C. Ng, John P. Cooke, Sanjay Patel

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Background Endothelial cells derived from human induced pluripotent stem cells (iPSC-ECs) promote angiogenesis, and more recently induced endothelial cells (iECs) have been generated via fibroblast trans-differentiation. These cell types have potential as treatments for peripheral arterial disease (PAD). However, it is unknown whether different reprogramming methods produce cells that are equivalent in terms of their pro-angiogenic capabilities. Objectives We aimed to directly compare iPSC-ECs and iECs in an animal model of PAD, in order to identify which cell type, if any, displays superior therapeutic potential. Methods IPSC-ECs and iECs were generated from human fibroblasts, and transduced with a reporter construct encoding GFP and firefly luciferase for bioluminescence imaging (BLI). Endothelial phenotype was confirmed using in vitro assays. NOD-SCID mice underwent hindlimb ischaemia surgery and received an intramuscular injection of either 1 × 106 iPSC-ECs, 1 × 106 iECs or control vehicle only. Perfusion recovery was measured by laser Doppler. Hindlimb muscle samples were taken for histological analyses. Results Perfusion recovery was enhanced in iPSC-EC treated mice on day 14 (Control vs. iPSC-EC; 0.35 ± 0.04 vs. 0.54 ± 0.08, p < 0.05) and in iEC treated mice on days 7 (Control vs. iEC; 0.23 ± 0.02 vs. 0.44 ± 0.06, p < 0.05), 10 (0.31 ± 0.04 vs. 0.64 ± 0.07, p < 0.001) and 14 (0.35 ± 0.04 vs. 0.68 ± 0.07, p < 0.001) post-treatment. IEC-treated mice also had greater capillary density in the ischaemic gastrocnemius muscle (Control vs. iEC; 125 ± 10 vs. 179 ± 11 capillaries/image; p < 0.05). BLI detected iPSC-EC and iEC presence in vivo for two weeks post-treatment. Conclusions IPSC-ECs and iECs exhibit similar, but not identical, endothelial functionality and both cell types enhance perfusion recovery after hindlimb ischaemia.

Original languageEnglish (US)
Pages (from-to)81-89
Number of pages9
JournalInternational Journal of Cardiology
Volume234
DOIs
StatePublished - May 1 2017

Keywords

  • Angiogenesis
  • Cell therapy
  • Differentiation
  • Endothelial cells
  • Peripheral arterial disease
  • Reprogramming

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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