Exosome-mediated inhibition of microRNA-449a promotes the amplification of mouse retinal progenitor cells and enhances their transplantation in retinal degeneration mouse models

Chen Jun Guo; Xiu Li Cao; Yu Fei Zhang; Kang Yi Yue; Jing Han; Hong Yan; Hua Han; Min Hua Zheng

doi:10.1016/j.omtn.2023.02.015

Exosome-mediated inhibition of microRNA-449a promotes the amplification of mouse retinal progenitor cells and enhances their transplantation in retinal degeneration mouse models

Mol Ther Nucleic Acids. 2023 Feb 16:31:763-778. doi: 10.1016/j.omtn.2023.02.015. eCollection 2023 Mar 14.

Authors

Chen Jun Guo^{1

2}, Xiu Li Cao³, Yu Fei Zhang³, Kang Yi Yue³, Jing Han¹, Hong Yan⁴, Hua Han², Min Hua Zheng³

Affiliations

¹ Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, Shaanxi, China.
² Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
³ Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
⁴ Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated Guangren Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China.

Abstract

Inherited and age-related retinal degenerations are the commonest causes of blindness without effective treatments. Retinal progenitor cells (RPCs), which have the multipotency to differentiate into various retinal cell types, are regarded as a promising source of cell transplantation therapy for retinal degenerative diseases. However, the self-limited expansion of RPCs causes difficulty in cell source supply and restrict its clinical treatment. In this work, we found that inhibition of microRNA-449a (miR-449a) in RPCs can promote proliferation and inhibit apoptosis of RPCs, partially through upregulating Notch signaling. Further optimization of transduction miR-449a inhibitor into RPCs by endothelial cell-derived exosomes can promote the survival of RPCs transplanted in vivo and reduce cell apoptosis in retinal degeneration mouse models. In summary, these studies have shown that exosome-miR-449a inhibitor can effectively promote the expansion of RPCs in vitro and enhance transplanted RPCs survival in vivo, which might provide a novel intervention strategy for retinal degenerations in the future.

Keywords: MT: Special Issue - Exploiting Extracellular Vesicles as Therapeutic Agents; Notch signaling; exosome; miR-449a; retinal degeneration; retinal progenitor cells.