Bioactive extracellular vesicles from a subset of endothelial progenitor cells rescue retinal ischemia and neurodegeneration
Kyle V. Marra, … , Susumu Sakimoto, Martin Friedlander
Kyle V. Marra, … , Susumu Sakimoto, Martin Friedlander
Published May 31, 2022
Citation Information: JCI Insight. 2022;7(12):e155928. https://doi.org/10.1172/jci.insight.155928.
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Research Article Ophthalmology Vascular biology

Bioactive extracellular vesicles from a subset of endothelial progenitor cells rescue retinal ischemia and neurodegeneration

Abstract

Disruption of the neurovascular unit (NVU) underlies the pathophysiology of various CNS diseases. One strategy to repair NVU dysfunction uses stem/progenitor cells to provide trophic support to the NVU’s functionally coupled and interdependent vasculature and surrounding CNS parenchyma. A subset of endothelial progenitor cells, endothelial colony-forming cells (ECFCs) with high expression of the CD44 hyaluronan receptor (CD44hi), provides such neurovasculotrophic support via a paracrine mechanism. Here, we report that bioactive extracellular vesicles from CD44hi ECFCs (EVshi) are paracrine mediators, recapitulating the effects of intact cell therapy in murine models of ischemic/neurodegenerative retinopathy; vesicles from ECFCs with low expression levels of CD44 (EVslo) were ineffective. Small RNA sequencing comparing the microRNA cargo from EVshi and EVslo identified candidate microRNAs that contribute to these effects. EVshi may be used to repair NVU dysfunction through multiple mechanisms to stabilize hypoxic vasculature, promote vascular growth, and support neural cells.

Authors

Kyle V. Marra, Edith Aguilar, Guoqin Wei, Ayumi Usui-Ouchi, Yoichiro Ideguchi, Susumu Sakimoto, Martin Friedlander

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Figure 4

EVshi provide neurovasculotrophic support to inherited retinal degeneration mice.

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EVshi provide neurovasculotrophic support to inherited retinal degenerat...
(A) Representative images of the deep vascular plexus in Isolectin Griffonia simplicifolia-IB4–stained (GS-IB4–stained) flat-mounted P25 and P60 retinas of RD10 mice treated on P14 with either EVshi or EVslo or untreated mice. Scale bar: 100 μm. (B) Treatment of RD10 mice with EVshi delayed vascular atrophy. Quantification of the branching points (left), total vessel area (middle), and total vessel length (right) in the deep vascular plexus at P21, P25, P32, P40, and P60 demonstrated EVshi delayed atrophy of the deep vascular plexus. One-way ANOVA with Tukey’s analysis; n = 5–9 retinas in EV groups, n = 8–14 retinas in untreated groups. Error bars represent SEM. (C) Immunohistochemistry of retinal cross sections harvested on P28 from RD10 mice treated P14 demonstrated a neuroprotective role of EVshi. Quantification of the ONL thickness (left) and density of apoptosis in the ONL via TUNEL staining (right). One-way ANOVA with Tukey’s analysis; n = 13 retinas for EVshi, n = 9 retinas for EVslo, n = 10 retinas for PBS, n = 8 retinas for untreated. (D) EVshi promoted functional rescue of the neural retina in RD10 mice. ERG measurements on P42 showed pronounced and lasting improvement in both dark-adapted (rod-driven scotopic B wave, left) and light-adapted (cone-driven flicker response, right) retinal function following P14 treatment with EVshi. One-way ANOVA with Tukey’s analysis; n = 12–14 retinas for EVshi, n = 12–14 retinas for EVslo, n = 12 retinas for PBS, n = 20–22 retinas for untreated. Error bars in all figures represent SEM. (E) Representative waveforms of the mean ERG readings on P28 of RD10 mice treated on P14 with EVshi, EVslo, or PBS or untreated. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.