Targeted delivery of human iPS-ECs overexpressing IL-8 receptors inhibits neointimal and inflammatory responses to vascular injury in the rat

Samantha Giordano, Xiangmin Zhao, Daisy Xing, Fadi Hage, Suzanne Oparil, John P. Cooke, Jieun Lee, Karina H. Nakayama, Ngan F. Huang, Yiu Fai Chen

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a chemoattractant for neutrophils which express IL8 receptors IL8RA and RB (IL8RA/B) on their membranes. Neutrophils interact with the damaged endothelium and initiate an inflammatory cascade at the site of injury. We have generated a novel translational targeted cell therapy for acute vascular injury using adenoviral vectors to overexpress IL8RA/B and green fluorescent protein (GFP) on the surface of endothelial cells (ECs) derived from human induced pluripotent stem cells (HiPS-IL8RA/B-ECs). We hypothesize that HiPS-IL8RA/B-ECs transfused intravenously into rats with balloon injury of the carotid artery will target to the injured site and compete with neutrophils, thus inhibiting inflammation and neointima formation. Young adult male Sprague-Dawley rats underwent balloon injury of the right carotid artery and received intravenous transfusion of saline vehicle, 1.5 × 106 HiPS-ECs, 1.5 × 106 HiPS-Null-ECs, or 1.5 × 106 HiPS-IL8RA/B-ECs immediately after endoluminal injury. Tissue distribution of HiPS-IL8RA/B-ECs was analyzed by a novel GFP DNA qPCR method. Cytokine and chemokine expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 h postinjury by ELISA and immunohistochemistry, respectively. Neointimal, medial areas, and reendothelialization were measured 14 days postinjury. HiPS-IL8RA/B-ECs homed to injured arteries, inhibited inflammatory mediator expression and inflammatory cell infiltration, accelerated reendothelialization, and attenuated neointima formation after endoluminal injury while control HiPS-ECs and HiPS-Null-ECs did not. HiPS-IL8RA/B-ECs transfused into rats with endoluminal carotid artery injury target to the injured artery and provide a novel strategy to treat vascular injury.

Original languageEnglish (US)
Pages (from-to)H705-H715
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume310
Issue number6
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

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Interleukin-8 Receptors
Vascular System Injuries
Endothelial Cells
Carotid Artery Injuries
Arteries
Neointima
Null Lymphocytes
Neutrophils
Green Fluorescent Proteins
Wounds and Injuries
Induced Pluripotent Stem Cells
Chemotactic Factors
Tissue Distribution
Cell- and Tissue-Based Therapy
Interleukin-8
Chemokines
Endothelium
Sprague Dawley Rats
Young Adult

Keywords

  • Endothelial cells
  • Human induced pluripotent stem cells
  • Inflammation vascular injury
  • Restenosis
  • Targeted cell therapy
  • Vascular injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Targeted delivery of human iPS-ECs overexpressing IL-8 receptors inhibits neointimal and inflammatory responses to vascular injury in the rat. / Giordano, Samantha; Zhao, Xiangmin; Xing, Daisy; Hage, Fadi; Oparil, Suzanne; Cooke, John P.; Lee, Jieun; Nakayama, Karina H.; Huang, Ngan F.; Chen, Yiu Fai.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 310, No. 6, 01.03.2016, p. H705-H715.

Research output: Contribution to journalArticle

Giordano, Samantha ; Zhao, Xiangmin ; Xing, Daisy ; Hage, Fadi ; Oparil, Suzanne ; Cooke, John P. ; Lee, Jieun ; Nakayama, Karina H. ; Huang, Ngan F. ; Chen, Yiu Fai. / Targeted delivery of human iPS-ECs overexpressing IL-8 receptors inhibits neointimal and inflammatory responses to vascular injury in the rat. In: American Journal of Physiology - Heart and Circulatory Physiology. 2016 ; Vol. 310, No. 6. pp. H705-H715.
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AU - Hage, Fadi

AU - Oparil, Suzanne

AU - Cooke, John P.

AU - Lee, Jieun

AU - Nakayama, Karina H.

AU - Huang, Ngan F.

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AB - Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a chemoattractant for neutrophils which express IL8 receptors IL8RA and RB (IL8RA/B) on their membranes. Neutrophils interact with the damaged endothelium and initiate an inflammatory cascade at the site of injury. We have generated a novel translational targeted cell therapy for acute vascular injury using adenoviral vectors to overexpress IL8RA/B and green fluorescent protein (GFP) on the surface of endothelial cells (ECs) derived from human induced pluripotent stem cells (HiPS-IL8RA/B-ECs). We hypothesize that HiPS-IL8RA/B-ECs transfused intravenously into rats with balloon injury of the carotid artery will target to the injured site and compete with neutrophils, thus inhibiting inflammation and neointima formation. Young adult male Sprague-Dawley rats underwent balloon injury of the right carotid artery and received intravenous transfusion of saline vehicle, 1.5 × 106 HiPS-ECs, 1.5 × 106 HiPS-Null-ECs, or 1.5 × 106 HiPS-IL8RA/B-ECs immediately after endoluminal injury. Tissue distribution of HiPS-IL8RA/B-ECs was analyzed by a novel GFP DNA qPCR method. Cytokine and chemokine expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 h postinjury by ELISA and immunohistochemistry, respectively. Neointimal, medial areas, and reendothelialization were measured 14 days postinjury. HiPS-IL8RA/B-ECs homed to injured arteries, inhibited inflammatory mediator expression and inflammatory cell infiltration, accelerated reendothelialization, and attenuated neointima formation after endoluminal injury while control HiPS-ECs and HiPS-Null-ECs did not. HiPS-IL8RA/B-ECs transfused into rats with endoluminal carotid artery injury target to the injured artery and provide a novel strategy to treat vascular injury.

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KW - Restenosis

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