Zoe E Clayton1, Gloria S C Yuen2, Sara Sadeghipour3, Jack D Hywood4, Jack W T Wong5, Ngan F Huang6, Martin K C Ng7, John P Cooke8, Sanjay Patel9. 1. Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Camperdown, NSW 2006, Australia. Electronic address: Zoe.Clayton@hri.org.au. 2. Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Camperdown, NSW 2006, Australia. Electronic address: Gloria.Yuen@hri.org.au. 3. Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia. Electronic address: sara.sadeghipour81@gmail.com. 4. Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Camperdown, NSW 2006, Australia. Electronic address: Jack.Hywood@hri.org.au. 5. Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA. Electronic address: wwong@houstonmethodist.org. 6. Department of Cardiothoracic Surgery, Stanford University, Stanford, CA. Stanford Cardiovascular Institute, Stanford, CA, United States. Electronic address: ngantina@stanford.edu. 7. Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Camperdown, NSW 2006, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. Electronic address: Martin.Ng@hri.org.au. 8. Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA. Electronic address: jpcooke@houstonmethodist.org. 9. Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Camperdown, NSW 2006, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. Electronic address: Sanjay.Patel@hri.org.au.
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.
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.
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