The vasoreparative potential of endothelial colony-forming cells in the ischemic retina is enhanced by cibinetide, a non-hematopoietic erythropoietin mimetic

Olivia E. O'Leary, Paul Canning, Emma Reid, Pietro M. Bertelli, Stuart McKeown, Michael Brines, Anthony Cerami, Xuan Du, Heping Xu, Mei Chen, Louise Dutton, Derek P. Brazil, Reinhold J. Medina, Alan W. Stitt*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: Retinal ischemia remains a common sight threatening end-point in blinding diseases such as diabetic retinopathy and retinopathy of prematurity. Endothelial colony forming cells (ECFCs) represent a subpopulation of endothelial progenitors with therapeutic utility for promoting reparative angiogenesis in the ischaemic retina. The current study has investigated the potential of enhancing this cell therapy approach by the dampening of the pro-inflammatory milieu typical of ischemic retina. Based on recent findings that ARA290 (cibinetide), a peptide based on the Helix-B domain of erythropoietin (EPO), is anti-inflammatory and tissue-protective, the effect of this peptide on ECFC-mediated vascular regeneration was studied in the ischemic retina. Methods: The effects of ARA290 on pro-survival signaling and function were assessed in ECFC cultures in vitro. Efficacy of ECFC transplantation therapy to promote retinal vascular repair in the presence and absence of ARA290 was studied in the oxygen induced retinopathy (OIR) model of retinal ischemia. The inflammatory cytokine profile and microglial activation were studied as readouts of inflammation. Results: ARA290 activated pro-survival signaling and enhanced cell viability in response to H 2 O 2 -mediated oxidative stress in ECFCs in vitro. Preconditioning of ECFCs with EPO or ARA290 prior to delivery to the ischemic retina did not enhance vasoreparative function. ARA290 delivered systemically to OIR mice reduced pro-inflammatory expression of IL-1β and TNF-α in the mouse retina. Following intravitreal transplantation, ECFCs incorporated into the damaged retinal vasculature and significantly reduced avascular area. The vasoreparative function of ECFCs was enhanced in the presence of ARA290 but not EPO. Discussion: Regulation of the pro-inflammatory milieu of the ischemic retina can be enhanced by ARA290 and may be a useful adjunct to ECFC-based cell therapy for ischemic retinopathies.

Original languageEnglish
Pages (from-to)144-155
Number of pages12
JournalExperimental Eye Research
Volume182
Early online date12 Mar 2019
DOIs
Publication statusPublished - 01 May 2019

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Keywords

  • Angiogenesis
  • Endothelial progenitor cells
  • Erythropoietin
  • Innate repair receptor
  • Oxygen-induced retinopathy
  • Retinal ischemia

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