Effective treatment of optic neuropathies by intraocular delivery of MSC-sEVs through augmenting the G-CSF-macrophage pathway

Abstract

Purpose : Optic neuropathies, characterized by injury of retinal ganglion cell (RGC) axons of the optic nerve, cause incurable blindness worldwide. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) represent a promising ‘cell-free’ therapy for regenerative medicine; however, the therapeutic effect on neural restoration fluctuates, and the underlying mechanism is poorly understood.

Methods : We utilized an optic nerve crush mouse model to evaluate the effects of intraocular administrated MSC-sEVs on RGC survival and axon regeneration. ScRNA-seq, bulk RNA-seq, flow cytometry, an exosome-reporter and immunostaining were introduced to investigate the cellular mechanism of potential neural restoration effects.

Results : We illustrated that intraocular administration of MSC-sEVs promoted both RGC survival and axon regeneration. Mechanistically, MSC-sEVs primarily targeted retinal mural cells to release high levels of G-CSF that recruited a neural restorative population of Ly6C^low monocytes/monocyte-derived macrophages (Mo/MΦ). Intravitreal administration of G-CSF, a clinically proven agent for treating neutropenia, or donor Ly6C^low Mo/MΦ markedly improved neurological outcomes in vivo.

Conclusions : Our data define a novel mechanism of MSC-sEV-induced G-CSF-to-Ly6C^low Mo/MΦ signaling in repairing optic nerve injury and highlight local delivery of MSC-sEVs, G-CSF and Ly6C^lowMo/MΦ as new therapeutic paradigms for the treatment of optic neuropathies.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

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