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

• Published in: International journal of cardiology Vol. 234; pp. 81 - 89
• Main Authors: Clayton, Zoe E, Yuen, Gloria SC, Sadeghipour, Sara, Hywood, Jack D, Wong, Jack WT, Huang, Ngan F, Ng, Martin KC, Cooke, John P, Patel, Sanjay
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2017
• Subjects: Angiogenesis; Animals; Cardiovascular; Cell Differentiation - physiology; Cell therapy; Cells, Cultured; Cellular Reprogramming - physiology; Differentiation; Disease Models, Animal; Endothelial cells; Endothelial Cells - physiology; Fibroblasts - physiology; Hindlimb - blood supply; Humans; Induced Pluripotent Stem Cells - physiology; Ischemia - metabolism; Ischemia - therapy; Mice; Mice, Inbred NOD; Mice, SCID; Myocardial Perfusion Imaging - methods; Peripheral arterial disease; Peripheral Arterial Disease - metabolism; Peripheral Arterial Disease - physiopathology; Peripheral Arterial Disease - therapy; Reprogramming; Stem Cell Transplantation - methods; Treatment Outcome; Cell therapy; human coronary artery endothelial cell; non-obese diabetic/severe combined immunodeficiency; iEC; iPSC; bioluminescence imaging; peripheral arterial disease; induced endothelial cell; Endothelial cells; Angiogenesis; HCAEC; PAD; Reprogramming; induced pluripotent stem cell; iPSC-EC; NOD/SCID; Differentiation; BLI; induced pluripotent stem cell derived endothelial cell; Peripheral arterial disease
• DOI: 10.1016/j.ijcard.2017.01.125
• ISSN: 0167-5273

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 1x106 iPSC-ECs, 1x106 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.