Exosomes released from neural progenitor cells and induced neural progenitor cells regulate neurogenesis through miR-21a

Yizhao Ma,Jialin C Zheng,Yunlong Huang,Chunhong Li,Xiaohuan Xia,Yi Wang

doi:10.1186/s12964-019-0418-3

Abstract

Neural stem/progenitor cells (NPCs) are known to have potent therapeutic effects in neurological disorders through secreting exosomes. The limited numbers of NPCs in adult brain and the decline of NPC pool in many neurological disorders restrain the further use of exosomes in treating these diseases. The direct conversion of somatic cells into induced NPCs (iNPCs) provides abundant NPC-like cells to study the therapeutic effects of NPCs-originated exosomes (EXOs). Our recent study demonstrated that iNPCs-derived exosomes (iEXOs) exhibit distinct potential in facilitating the proliferation of NPCs, compared to EXOs, indicating the importance to investigate the effects of EXOs and iEXOs on the differentiation of NPCs, which remains unknown. Here, our results suggest that EXOs, but not iEXOs, promoted neuronal differentiation and neither of them had effect on glial generation. Microarray analysis revealed different miRNA signatures in EXOs and iEXOs, in which miR-21a was highly enriched in EXOs. Perturbation of function assay demonstrated the key roles of miR-21a in the generation of neurons and mediating the neurogenic potential of exosomes. Our data suggest that EXOs and iEXOs may achieve their therapeutic effects in promoting neurogenesis through transferring key miRNAs, which sheds light on the development of highly efficient cell-free therapeutic strategies for treating neurological diseases.

Highlights

Due to the failure of clinical trial of drugs for eliminating key risk factors (e.g. Aβ) of neurodegenerative disorders, transplantation of stem cells have been considered as a promising therapeutic strategy for treating these diseases [1, 2]
EXOs and induced Neural stem/progenitor cells (NPCs) (iNPCs)-derived exosomes (iEXOs) display differential effects on neuronal differentiation To test the influence of EXOs and iEXOs on the differentiation of NPCs, we first collected EXOs and iEXOs using ultracentrifugation-based approach
Exosomes were visualized under transmission electron microscopy (TEM), which displayed vesicle-like structures with sizes between 30 to 150 nm (Additional file 1: Figure S1A)

Summary

Introduction

Due to the failure of clinical trial of drugs for eliminating key risk factors (e.g. Aβ) of neurodegenerative disorders, transplantation of stem cells have been considered as a promising therapeutic strategy for treating these diseases [1, 2]. Due to the low survival, differentiation and integration efficiency of exogenous cells in the brain, recent findings suggested that transplanted cells might implement their therapeutic effects through secreting exosomes [8, 9]. Exogenous cells, such as mesenchymal stem cells (MSCs), could secrete exosomes, a key component of microenvironment, to promote neural plasticity and functional recovery in various central nervous system (CNS) disease models [9,10,11]. MSCs-derived exosomes contain high levels of miR-133b and miRNAs in miR-17~92 cluster which repress the expression of

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Discussion

Conclusion