Matrix-bound nanovesicles prevent ischemia-induced retinal ganglion cell axon degeneration and death and preserve visual function

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.

The Extracellular Matrix-Derived Biomarkers for Diagnosis, Prognosis, and Personalized Therapy of Malignant Tumors

“…MBVs are integral and distinct components of ECM, and their content is unique to cellular origin (78). Recently, it has been demonstrated that MBVs can suppress pro-inflammatory signaling in microglia and astrocytes (79). So far, the literature exists only on MBVs found in non-timorous ECM, but we propose that tumor-specific MBVs may also be found.…”

Biological properties and therapeutic effects of plant-derived nanovesicles

“…MBVs and their miRNA cargoes can recapitulate many of their parent ECM’s effects, including the promotion of a regulatory macrophage phenotype, thus facilitating tissue repair [ 22 ]. In addition, MBVs have been shown to positively regulate primary neuron survival and growth [ 25 ] as well as to reduce proinflammatory, neurotoxic glial signaling enhancing healing responses in the retina and the optic nerve [ 26 ]. Although PDNVs were initially conceived as more similar in structure and function to mammalian exosomes than MBVs [ 27 ], they are quite heterogeneous in size (see below) and may have distinct features from mammalian exosomes and MBVs.…”

Applications of Manganese-Enhanced Magnetic Resonance Imaging in Ophthalmology and Visual Neuroscience

“…Manganese-enhanced MRI also provides a solution to non-invasively image transport deficits in the visual system for examining neuronal abnormalities caused by optic neuropathies such as irradiation-induced injuries (Ryu et al, 2002), optic nerve crush (Thuen et al, 2005; Fischer et al, 2014), glaucoma (Chan et al, 2007, 2008c; Fiedorowicz et al, 2018; Yang et al, 2018), optic neuritis (Lin et al, 2014b), retinal ischemia/reperfusion (van der Merwe et al, 2019), and neonatal hypoxia-ischemia (Chan et al, 2014b). Studies by Thuen et al (2005, 2009) are among the earliest to demonstrate the feasibility of MEMRI for longitudinal monitoring of Mn 2+ transport along injured axons of the central visual pathway via intraocular Mn 2+ administration.…”

“…Subsequent studies demonstrated the use of in vivo MEMRI tract tracing for retinotopic mapping at submillimeter resolution (Chan et al, 2011) (Figure 3B), and for monitoring primary versus secondary degeneration after partial transection of the optic nerve (Chan et al, 2017). With these premises, MEMRI can serve as an in vivo imaging model system to evaluate neuroprotective approaches to the injured visual system (Mansergh et al, 2014; Van der Merwe et al, 2016, van der Merwe et al, 2019), as well as to trace neuroplasticity (Immonen et al, 2008; Chan et al, 2012a; Tang et al, 2017b) and regenerated axons along the visual pathway (Liang et al, 2011; Sandvig et al, 2011, 2012; Sandvig and Sandvig, 2014; Komatsu et al, 2017). MEMRI can be combined with diffusion tensor imaging to give complementary information about injury and regeneration in the adult optic nerve (Thuen et al, 2009).…”

“…While MnCl 2 can stimulate the microglia dose-dependently (Zhang et al, 2007), it is also possible that systemic Mn 2+ administration at low doses could exert anti-oxidative effects to some extent and preserve brain tissues at remote sites from delayed secondary damage (Singh et al, 1992; Hussain and Ali, 1999; Chan et al, 2008a, 2017). There are currently a number of approaches to mediate neurodegeneration via targeting astrocytes and microglia (Yun et al, 2018; Liddelow and Sofroniew, 2019; van der Merwe et al, 2019). With better understanding of the Mn contrast mechanisms and careful interpretation, the combined Mn administration and MRI detection approaches may be useful for future investigations of post-injury cellular events and functional reorganization.…”