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.
Highlights
The World Health Organization predicts that traumatic brain injury (TBI) will surpass many diseases, including infectious diseases, as the major cause of death and disability by the year 2020 [1].It is estimated that about 10–20 million individuals are affected annually by TBI, of which 62% come from automobile vehicle accidents, 10% from sports injuries, and about 2–5% are due to war related injuries [1,2]
In this study, using a well-established mild TBI mouse model [10,33], we have evaluated whether the intravitreal injection of AAddiippoosse Derived Stromal Cell (ASC) concentrated conditioned medium (ASC-CCM) can rescue the visual deficits in TBI
TNFα and IL-1β are known to induce the expression of the anti-inflammatory protein TNF-stimulated gene 6 protein (TSG-6)
Summary
The World Health Organization predicts that traumatic brain injury (TBI) will surpass many diseases, including infectious diseases, as the major cause of death and disability by the year 2020 [1]. The secondary displacement of brain tissue can cause acceleration–deceleration injury, further exacerbating the primary pathology in blast or vehicular-related accidents. Glial cells in combination with endothelial cells and pericytes are known to function in the protection of retinal barrier integrity Any loss of such retinal barrier integrity is associated with a cycle of inflammation, vascular damage, and cell death. Isolation and expansion of a well-defined population of MSCs may be required for effective therapies as intravitreal injections of poorly defined stromal vascular fraction that contain ASCs has caused retinal detachment and visual loss in patients with age-related macular degeneration [21,22]. Our study demonstrates proteins that are upregulated in the ASC-CCM when ASCs are pre-stimulated with inflammatory cytokines can suppress microglial activation and protect retinal barrier integrity
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