4.6 Article

Uptake and Distribution of Administered Bone Marrow Mesenchymal Stem Cell Extracellular Vesicles in Retina

Journal

CELLS
Volume 10, Issue 4, Pages -

Publisher

MDPI
DOI: 10.3390/cells10040730

Keywords

astrocytes; exosomes; extracellular vesicles; in vivo imaging; ischemia; microglia; retina; retinal ganglion cells

Categories

Funding

  1. National Institutes of Health (Bethesda, MD, USA) [EY028690, EY028690-02S1, DE027404, EY001792, UL1 TR002003, PP-1905-33986]
  2. Glaucoma Research Foundation Shaffer Grant (San Francisco, CA, USA)
  3. Biomedical Consortium (Chicago, IL, USA)
  4. Department of Veterans Affairs (Washington, DC, USA) [BX004852-03, BX002625-06]
  5. National Glaucoma Grant from the Bright Focus Foundation (Clarksburg, MD, USA) [G2018168]
  6. Illinois Society for the Prevention of Blindness (Chicago, IL, USA)
  7. University of Illinois at Chicago Honors College Research Awards
  8. Michael Reese Foundation (Chicago, IL, USA)

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Mesenchymal Stem Cell Exosomes/Extracellular Vesicles (MSC EVs) are a promising alternative for treating retinal diseases, promoting immunomodulation, repair, and regeneration. Studies in rats and in vitro experiments have shown that intravitreally administered EVs are effective for treating diseases affecting the inner retina.
Cell replacement therapy using mesenchymal (MSC) and other stem cells has been evaluated for diabetic retinopathy and glaucoma. This approach has significant limitations, including few cells integrated, aberrant growth, and surgical complications. Mesenchymal Stem Cell Exosomes/Extracellular Vesicles (MSC EVs), which include exosomes and microvesicles, are an emerging alternative, promoting immunomodulation, repair, and regeneration by mediating MSC's paracrine effects. For the clinical translation of EV therapy, it is important to determine the cellular destination and time course of EV uptake in the retina following administration. Here, we tested the cellular fate of EVs using in vivo rat retinas, ex vivo retinal explant, and primary retinal cells. Intravitreally administered fluorescent EVs were rapidly cleared from the vitreous. Retinal ganglion cells (RGCs) had maximal EV fluorescence at 14 days post administration, and microglia at 7 days. Both in vivo and in the explant model, most EVs were no deeper than the inner nuclear layer. Retinal astrocytes, microglia, and mixed neurons in vitro endocytosed EVs in a dose-dependent manner. Thus, our results indicate that intravitreal EVs are suited for the treatment of retinal diseases affecting the inner retina. Modification of the EV surface should be considered for maintaining EVs in the vitreous for prolonged delivery.

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