Induced Pluripotent Stem Cell-Derived Endothelial Cells Overexpressing Interleukin-8 Receptors A/B and/or C-C Chemokine Receptors 2/5 Inhibit Vascular Injury Response.

Abstract

Recruitment of neutrophils and monocytes/macrophages to the site of vascular injury is mediated by binding of chemoattractants to interleukin (IL) 8 receptors RA and RB (IL8RA/B) C-C chemokine receptors (CCR) 2 and 5 expressed on neutrophil and monocyte/macrophage membranes. Endothelial cells (ECs) derived from rat-induced pluripotent stem cells (RiPS) were transduced with adenovirus containing cDNA of IL8RA/B and/or CCR2/5. We hypothesized that RiPS-ECs overexpressing IL8RA/B (RiPS-IL8RA/B-ECs), CCR2/5 (RiPS-CCR2/5-ECs), or both receptors (RiPS-IL8RA/B+CCR2/5-ECs) will inhibit inflammatory responses and neointima formation in balloon-injured rat carotid artery. Twelve-week-old male Sprague-Dawley rats underwent balloon injury of the right carotid artery and intravenous infusion of (a) saline vehicle, (b) control RiPS-Null-ECs (ECs transduced with empty virus), (c) RiPS-IL8RA/B-ECs, (d) RiPS-CCR2/5-ECs, or (e) RiPS-IL8RA/B+CCR2/5-ECs. Inflammatory mediator expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 hours postinjury by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. Neointima formation was assessed at 14 days postinjury. RiPS-ECs expressing the IL8RA/B or CCR2/5 homing device targeted the injured arteries and decreased injury-induced inflammatory cytokine expression, neutrophil/macrophage infiltration, and neointima formation. Transfused RiPS-ECs overexpressing IL8RA/B and/or CCR2/5 prevented inflammatory responses and neointima formation after vascular injury. Targeted delivery of iPS-ECs with a homing device to inflammatory mediators in injured arteries provides a novel strategy for the treatment of cardiovascular diseases. Stem Cells Translational Medicine 2017;6:1168-1177.

• Authors: Samantha Giordano, Xiangmin Zhao, Yiu-Fai Chen, Silvio H Litovsky, Fadi G Hage, Tim M Townes, Chiao-Wang Sun, Li-Chen Wu, Suzanne Oparil, Dongqi Xing
• Journal: Stem cells translational medicine (Stem Cells Transl Med) Vol. 6 Issue 4 Pg. 1168-1177 (04 2017) ISSN: 2157-6564 [Print] England
• PMID: 28233474 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Chemical References

• Receptors, CCR2
• Receptors, CCR5
• Receptors, Interleukin-8

Topics

• Animals
• Cell- and Tissue-Based Therapy
• Endothelial Cells (cytology, metabolism)
• Induced Pluripotent Stem Cells (cytology, metabolism)
• Inflammation (metabolism)
• Macrophages (metabolism)
• Male
• Neutrophils (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, CCR2 (metabolism)
• Receptors, CCR5 (metabolism)
• Receptors, Interleukin-8 (metabolism)
• Vascular System Injuries (metabolism, therapy)