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

• 成果类型: Article
• 署名作者: Yi, Wei; Xue, Ying; Qing, Wenjie; Cao, Yingxue; Zhou, Lingli; Xu, Mingming; Sun, Zehui; Li, Yuying; Mai, Xiaomei; Shi, Le; He, Chang; Zhang, Feng; Duh, Elia J.; Cao, Yihai; Liu, Xialin
• 署名单位: Sun Yat Sen University; Johns Hopkins University; Johns Hopkins Medicine; Karolinska Institutet
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11194
• DOI: 10.1073/pnas.2305947121
• 发表日期: 2024-02-06
• 关键词: mesenchymal stem-cells; axon regeneration; pericytes

摘要

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. Here, we illustrated that intraocular administration of MSC-sEVs promoted both RGC survival and axon regeneration in an optic nerve crush mouse model. Mechanistically, MSC-sEVs primarily targeted retinal mural cells to release high levels of colony- stimulating factor 3 (G-CSF) that recruited a neural restorative population of Ly6Clow monocytes/monocyte- derived macrophages (Mo/M(13). Intravitreal administration of G-CSF, a clinically proven agent for treating neutropenia, or donor Ly6Clow Mo/M(13 markedly improved neurological outcomes in vivo. Together, our data define a unique mechanism of MSC-sEV- induced G- CSF- to- Ly6Clow Mo/M(13 signaling in repairing optic nerve injury and highlight local delivery of MSC-sEVs, G-CSF, and Ly6Clow Mo/M(13 as therapeutic paradigms for the treatment of optic neuropathies.