Abstract
Injury to retinal ganglion cells (RGC), central nervous system neurons that relay visual information to the brain, often leads to RGC axon degeneration and permanently lost visual function. Herein this study shows matrix-bound nanovesicles (MBV), a distinct class of extracellular nanovesicle localized specifically to the extracellular matrix (ECM) of healthy tissues, can neuroprotect RGCs and preserve visual function after severe, intraocular pressure (IOP) induced ischemia in rat. Intravitreal MBV injections attenuated IOP-induced RGC axon degeneration and death, protected RGC axon connectivity to visual nuclei in the brain, and prevented loss in retinal function as shown by histology, anterograde axon tracing, manganese-enhanced magnetic resonance imaging, and electroretinography. In the optic nerve, MBV also prevented IOP-induced decreases in growth associated protein-43 and IOP-induced increases in glial fibrillary acidic protein. In vitro studies showed MBV suppressed pro-inflammatory signaling by activated microglia and astrocytes, stimulated RGC neurite growth, and neuroprotected RGCs from neurotoxic media conditioned by pro-inflammatory astrocytes. Thus, MBV can positively modulate distinct signaling pathways (e.g., inflammation, cell death, and axon growth) in diverse cell types. Since MBV are naturally derived, bioactive factors present in numerous FDA approved devices, MBV may be readily useful, not only experimentally, but also clinically as immunomodulatory, neuroprotective factors for treating trauma or disease in the retina as well as other CNS tissues.
Highlights
Injury to retinal ganglion cells (RGC), central nervous system neurons that relay visual information to the brain, often leads to RGC axon degeneration and permanently lost visual function
matrix-bound nanovesicles (MBV) are a distinct class of extracellular vesicle localized to collagen fibrils within the extracellular matrix (ECM) of all experimental and commercial ECM bioscaffolds analyzed to date[9]
This study reports on the effects of MBV on primary microglia, astrocytes, and RGCs in vitro and, on RGC viability, RGC axon integrity and connectivity to visual nuclei in the brain, and visual function after severe intraocular pressure (IOP) induced ischemia
Summary
Injury to retinal ganglion cells (RGC), central nervous system neurons that relay visual information to the brain, often leads to RGC axon degeneration and permanently lost visual function. After retina or optic nerve injury, microglia are hypothesized to polarize toward a pro-inflammatory, M1-like, phenotype and secrete, among other factors, tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and complement protein C1q3. These factors, in turn, are thought to act directly[4] and indirectly on RGCs by inducing an A1-like, neurotoxic phenotype in astrocytes that signals RGC axon degeneration and death[5]. MBV can deliver cargo to diverse cell types, and purified MBV can recapitulate many of their parent ECM’s effects, including polarizing cells underlying the innate immune response toward an anti-inflammatory phenotype[13] and differentially regulating primary CNS neuron survival and growth[14]
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