July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Extracellular vesicles shed from endothelial colony forming cells (ECFCs) with high expression of CD44 are paracrine mediators of neurovasculotrophic retinal repair
Author Affiliations & Notes
  • Kyle Vincent Marra
    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States
    School of Medicine, University of California, San Diego, La Jolla, California, United States
  • Edith Aguilar
    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States
  • Ayumi Ouchi
    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States
  • Susumu Sakimoto
    Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan
  • Martin Friedlander
    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States
  • Footnotes
    Commercial Relationships   Kyle Marra, None; Edith Aguilar, None; Ayumi Ouchi, None; Susumu Sakimoto, None; Martin Friedlander, None
  • Footnotes
    Support  The Lowy Medical Research Institute; National Institutes of Health Ruth L. Kirschstein National Research Service Award 1F30EY029141 – 01 from the National Eye Institute; University of California, San Diego Medical Scientist Training Program T32 GM007198-40
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 6389. doi:https://doi.org/
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    • Get Citation

      Kyle Vincent Marra, Edith Aguilar, Ayumi Ouchi, Susumu Sakimoto, Martin Friedlander; Extracellular vesicles shed from endothelial colony forming cells (ECFCs) with high expression of CD44 are paracrine mediators of neurovasculotrophic retinal repair. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6389. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : ECFCs are a subset of endothelial progenitor cells that promote vascular growth and stability. ECFCs with high expression of the hyaluronan receptor CD44 (CD44hi) rescue the oxygen-induced retinopathy (OIR) model and rd10 mice via paracrine action while ECFCs with low CD44 expression (CD44lo) have little effect. In this study, we describe an ECFC extracellular vesicle (EV)-mediated paracrine mechanism that recapitulates the enhanced neuro- and vasculotrophic effects of CD44hi cells in the OIR and rd10 model.

Methods : EVs were harvested from media conditioned by CD44hi and CD44lo umbilical cord blood-derived ECFCs via a series of ultrafiltration and size exclusion chromatography prior to injection into the OIR or rd10 model. Therapeutic EVs from CD44hi ECFCs and ineffective CD44lo EVs were subject to small RNA sequencing to identify intravesicular cargo that may mediate this effect.

Results : In OIR, CD44hi EVs from all 3 of 3 umbilical cord blood donors significantly reduced the area of retinal neovascularization and vaso-obliteration relative to CD44lo EVs. Depletion of EVs from the sample via ultracentrifugation ameliorated this effect. Dose response experiments indicated CD44hi EV samples derived our novel isolation protocol retained efficacy even after 10,000-fold dilution of the sample. In rd10 mice, injection of CD44hi EVs significantly reduced vessel loss in the intermediate and deep vascular plexuses, decreased apoptosis in the outer nuclear layer (ONL), preserved ONL thickness, and improved retinal function on electroretinography relative to CD44lo EV, vehicle, or untreated controls. Small RNA sequencing analyses identified agents that may mediate the therapeutic effect of CD44hi EVs.

Conclusions : By comparing the bioactive cargo of EVs from therapeutic CD44hi ECFCs in comparison to ineffective CD44lo EVs, our “-omics” based approach may be used to identify microRNAs that promote the CD44hi EV-mediated rescue effect in the OIR and rd10 model. EVs may be a highly effective drug delivery vehicle targeting multiple cell types with multiple mechanisms simultaneously while circumventing the risks of tumorigenesis associated with intact cell-based therapeutics.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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