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Progenitor cell combination normalizes retinal vascular development in the oxygen-induced retinopathy (OIR) model
Sergio Li Calzi, … , Mervin C. Yoder, Maria B. Grant
Sergio Li Calzi, … , Mervin C. Yoder, Maria B. Grant
Published November 1, 2019
Citation Information: JCI Insight. 2019;4(21):e129224. https://doi.org/10.1172/jci.insight.129224.
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Categories: Research Article Angiogenesis Stem cells

Progenitor cell combination normalizes retinal vascular development in the oxygen-induced retinopathy (OIR) model

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Abstract

Retinopathy of prematurity (ROP) is a disorder of the developing retina of preterm infants. ROP can lead to blindness because of abnormal angiogenesis that is the result of suspended vascular development and vaso-obliteration leading to severe retinal stress and hypoxia. We tested the hypothesis that the use of the human progenitor cell combination, bone marrow–derived CD34+ cells and vascular wall–derived endothelial colony–forming cells (ECFCs), would synergistically protect the developing retinal vasculature in a mouse model of ROP, called oxygen-induced retinopathy (OIR). CD34+ cells alone, ECFCs alone, or the combination thereof were injected intravitreally at either P5 or P12 and pups were euthanized at P17. Retinas from OIR mice injected with ECFCs or the combined treatment revealed formation of the deep vascular plexus (DVP) while still in hyperoxia, with normal-appearing connections between the superficial vascular plexus (SVP) and the DVP. In addition, the combination of cells completely prevented aberrant retinal neovascularization and was more effective anatomically and functionally at rescuing the ischemia phenotype than either cell type alone. We show that the beneficial effects of the cell combination are the result of their ability to orchestrate an acceleration of vascular development and more rapid ensheathment of pericytes on the developing vessels. Lastly, our proteomic and transcriptomic data sets reveal pathways altered by the dual cell therapy, including many involved in neuroretinal maintenance, and principal component analysis (PCA) showed that cell therapy restored OIR retinas to a state that was closely associated with age-matched normal retinas. Together, these data herein support the use of dual cell therapy as a promising preventive treatment for the development of ROP in premature infants.

Authors

Sergio Li Calzi, Lynn C. Shaw, Leni Moldovan, William C. Shelley, Xiaoping Qi, Lyne Racette, Judith L. Quigley, Seth D. Fortmann, Michael E. Boulton, Mervin C. Yoder, Maria B. Grant

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Figure 5

The combination of ECFCs and CD34+ cells increases pericyte ensheathment in the OIR model.

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The combination of ECFCs and CD34+ cells increases pericyte ensheathment...
(A) Representative fluorescence images showing retinal blood vessels stained for collagen IV (red). Pericytes (yellow arrowheads) are easily recognizable as they appear as areas that are “bulging out” of the blood vessels. Blue arrowhead: small vascular tuft. Scale bar: 50 μm. (B) Representative fluorescence high magnification image showing that collagen IV (red) allows the identification of pericytes (yellow arrowheads). Scale bar: 10 μm. Blue stain is DAPI. (C) Quantification of pericytes in retina blood vessels of OIR mouse pups injected at P5 and analyzed at P17. Values are expressed as average/100 μm ± SEM. All data were assessed using 1-way ANOVA. When the results were significant, we determined which means differed from each other using Tukey’s multiple-comparisons test. Only significant comparisons are shown in the figures. Vehicle, n = 9; CD34, n = 12; ECFC, n = 7; ECFC/CD34, n = 6.
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Copyright © 2019 American Society for Clinical Investigation
ISSN 2379-3708

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