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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

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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 6

Effects of CD44hi ECFCs and EVshi in OIR mice are reduced following DICER1 KD.

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Effects of CD44hi ECFCs and EVshi in OIR mice are reduced following DICE...
DICER1 KD attenuated rescue effects of CD44hi ECFCs in A and B and their EVs in C and D in OIR mice. (A) Representative images and (B) quantification of NV and VO in retinal flat mounts from OIR mice demonstrated that CD44hi ECFCs-shDICER1 failed to rescue NV relative to mice treated with scrRNA-transfected control cells (CD44hi ECFCs-scrRNA). (C) Representative images and (D) quantification of retinal flat mounts demonstrated that EVs from CD44hi ECFCs-shDICER1 failed to rescue both NV and VO relative to mice treated with EVs from CD44hi ECFCs-scrRNA EVs. Two-tailed Student’s t test; n = 10 retinas for CD44hi ECFCs-scrRNA, n = 9 retinas for CD44hi ECFCs-shDICER1, n = 28 retinas for CD44hi ECFCs-scrRNA EVs, n = 18 retinas for CD44hi ECFCs-DICER1 EVs. Error bars represent SEM. *P < 0.05, ****P < 0.0001.

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