September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Evidence for a Glymphatic System in Human, Primate, Rat and Mouse Retina
Author Affiliations & Notes
  • Ping Hu
    Ophthalmology, IUPUI, Indianapolis, Indiana, United States
  • F Arfuso
    Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, Western Australia, Australia
  • Michele C Madigan
    Anatomy, University of New South Wales, Sydney, New South Wales, Australia
  • S Adamson
    Anatomy, School of Medical Sciences, Bosch Institute, Sydney, New South Wales, Australia
  • Lynn C Shaw
    Ophthalmology, IUPUI, Indianapolis, Indiana, United States
  • Michael E Boulton
    Ophthalmology, IUPUI, Indianapolis, Indiana, United States
  • Maria B Grant
    Ophthalmology, IUPUI, Indianapolis, Indiana, United States
  • Tailoi Chan-Ling
    Anatomy, School of Medical Sciences, Bosch Institute, Sydney, New South Wales, Australia
  • Footnotes
    Commercial Relationships   Ping Hu, None; F Arfuso, None; Michele Madigan, None; S Adamson, None; Lynn Shaw, None; Michael Boulton, None; Maria Grant, None; Tailoi Chan-Ling, None
  • Footnotes
    Support  NIH grants: R01EY0126001, R01EY007739, R01HL110170, R01DK090730. Research to Prevent Blindness Unrestricted grant awarded to the Department of Ophthalmology at IUPUI.
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Ping Hu, F Arfuso, Michele C Madigan, S Adamson, Lynn C Shaw, Michael E Boulton, Maria B Grant, Tailoi Chan-Ling; Evidence for a Glymphatic System in Human, Primate, Rat and Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2016;57(12):No Pagination Specified.

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

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Purpose : The ‘glymphatic’ system is a functional waste clearance pathway for the CNS, characterised by AQP4+ astrocytic endfeet in the peri-vascular space and the movement of fluids through extracellular space. Evidence for a glymphatic system in the human CNS, especially in the retina, remains to be elucidated. This study investigated the presence of a glymphatic system in human, primate, rat, and mouse retinas.

Methods : Retinas (39 human, including 9 from donors with a diabetes; 3 primate; 10 rat, and 10 mice) were fixed in 2-4% paraformaldehyde, and then examined using multimarker immunohistochemistry for glial fibrillary acidic protein (GFAP), vimentin, AQP4, CD39, Ulex europaeus agglutinin (UEA) Lectin, Griffonia simplicifolia (Bandeiraea) isolectin B4 (GS Lectin), podoplanin, VEGFR3, Prox-1, and LYVE-1.

Results : AQP4 was expressed by vimentin+ Müller cells and GFAP+ astrocytes in all retinas, with similar distributions and patterns. AQP4+/vimentin+ Müller cells and AQP4+/GFAP+ astrocytes formed a network that completely ensheathed the entire CD39+/Lectin+ blood vessel system in the retinas; however, many AQP4+ /CD39-/lectin- structures with lumens were evident between blood vessels. AQP4+/vimentin+ Müller cells mostly co-localized with podoplanin (lymphatic marker) predominantly around arterioles. Lymph nodes from rats demonstrated AQP4+/podoplanin+ lymphatic channels. Lectin+ blood vessels just outside the lymph node were AQP4-. Human diabetic retinas showed: 1) 1.7 fold increased expression of AQP4 on vimentin+ Müller cells (p<0.05) and 1.4 fold increased expression of podoplanin (p<0.05) compared to non-diabetic retina; 2) AQP4+ macrophage-like cells (4/9) that formed networks along large blood vessels in the inner retina adjacent to the vitreous; and 3) AQP4+ vessels that also showed strong podoplanin expression.

Conclusions : An AQP4+ glial network ensheathed the entire retinal vascular system, including between vessels and may be the anatomical correlate of a retinal ‘glymphatic’ system. The absence of expression of established lymphatic markers suggests that this is a special lymphatic-like system with a major role played by the glial cells of the retina. The AQP4+ network showed podoplanin co-expression in non-diabetic retinas that was enhanced in diabetic retinas, suggesting overactive function of this system in diabetic retinopathy.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.


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