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Int. J. Mol. Sci. 2018, 19(7), 2016; https://doi.org/10.3390/ijms19072016

Concentrated Conditioned Media from Adipose Tissue Derived Mesenchymal Stem Cells Mitigates Visual Deficits and Retinal Inflammation Following Mild Traumatic Brain Injury

1
Department of Ophthalmology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
2
Cell Care Therapeutics, Inc., Monrovia, CA 91016, USA
3
Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
*
Author to whom correspondence should be addressed.
Received: 12 June 2018 / Revised: 3 July 2018 / Accepted: 9 July 2018 / Published: 11 July 2018
(This article belongs to the Special Issue Adipose Stem Cells)
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Abstract

Blast concussions are a common injury sustained in military combat today. Inflammation due to microglial polarization can drive the development of visual defects following blast injuries. In this study, we assessed whether anti-inflammatory factors released by the mesenchymal stem cells derived from adipose tissue (adipose stem cells, ASC) can limit retinal tissue damage and improve visual function in a mouse model of visual deficits following mild traumatic brain injury. We show that intravitreal injection of 1 μL of ASC concentrated conditioned medium from cells pre-stimulated with inflammatory cytokines (ASC-CCM) mitigates loss of visual acuity and contrast sensitivity four weeks post blast injury. Moreover, blast mice showed increased retinal expression of genes associated with microglial activation and inflammation by molecular analyses, retinal glial fibrillary acidic protein (GFAP) immunoreactivity, and increased loss of ganglion cells. Interestingly, blast mice that received ASC-CCM improved in all parameters above. In vitro, ASC-CCM not only suppressed microglial activation but also protected against Tumor necrosis alpha (TNFα) induced endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrate TSG-6 is highly expressed in ASC-CCM from cells pre-stimulated with TNFα and IFNγ but not from unstimulated cells. Our findings suggest that ASC-CCM mitigates visual deficits of the blast injury through their anti-inflammatory properties on activated pro-inflammatory microglia and endothelial cells. A regenerative therapy for immediate delivery at the time of injury may provide a practical and cost-effective solution against the traumatic effects of blast injuries to the retina. View Full-Text
Keywords: TBI; adult stem cells; TSG6; retinal ganglion cells; oxidative stress; TIMP1; microglia; trans-endothelial electrical resistance TBI; adult stem cells; TSG6; retinal ganglion cells; oxidative stress; TIMP1; microglia; trans-endothelial electrical resistance
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Jha, K.A.; Pentecost, M.; Lenin, R.; Klaic, L.; Elshaer, S.L.; Gentry, J.; Russell, J.M.; Beland, A.; Reiner, A.; Jotterand, V.; Sohl, N.; Gangaraju, R. Concentrated Conditioned Media from Adipose Tissue Derived Mesenchymal Stem Cells Mitigates Visual Deficits and Retinal Inflammation Following Mild Traumatic Brain Injury. Int. J. Mol. Sci. 2018, 19, 2016.

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