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Research Article

Exosomes derived from human adipose-derived stem cells ameliorate osteoporosis through miR-335-3p/Aplnr axis

Chunhui Sheng1,§, Xiaodong Guo1,§, Zhuqing Wan1, Xiaoqiang Bai1, Hao Liu1, Xiao Zhang1, Ping Zhang1, Yunsong Liu1, Wenyue Li2( ), Yongsheng Zhou1 ( ), Longwei Lv1( )
National Center of Stomatology & National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Key Laboratory of Digital Stomatology, Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China
Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China

§ Chunhui Sheng and Xiaodong Guo contributed equally to this work.

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Graphical Abstract

Exosomes derived from human adipose-derived stem cells (hASCs) cultured in osteogenic induction medium (O-Exos) enhanced the osteogenic differentiation of bone marrow-derived stem cells (BMSCs) from ovariectomy osteoporotic mice and inhibited osteoclastogenesis which resulted in the amelioration of the osteoporotic conditions, and the engineered O-Exos constructed by transfection of miR-335-3p inhibitor into the exosomes showed a better effect. The findings indicated that the ASC-exosome-based therapy brings new possibilities for osteoporosis treatment.

Abstract

Treatment of osteoporosis is still a challenge in clinic, which leads to an increasing social burden as the aging of population. Exosomes originated from human adipose-derived stem cells (hASCs) hold promise to promote osteogenic differentiation, thus may ameliorate osteoporosis. The main purpose of this study was to investigate the novel usage of hASC-derived exosomes in the treatment of osteoporosis and their underlying mechanism. Two types of exosomes, i.e., exosomes derived from hASCs cultured in proliferation medium (P-Exos) and osteogenic induction medium (O-Exos), were obtained. As compared with P-Exos, O-Exos could promote the osteogenic differentiation of mouse bone marrow-derived stem cells (mBMSCs) from osteoporotic mice in vitro and ameliorated osteoporosis in vivo. Then, microRNA (miRNA)-335-3p was identified to be the key differentially expressed microRNA between the two exosomes by small RNA sequencing, gene overexpression and knock-down, qRT-PCR, and dual-luciferase reporter assay, and Aplnr was confirmed to be the potential target gene of miRNA-335-3p. In addition, miR-335-3p inhibitor-optimized O-Exos were established by transfection of miR-335-3p inhibitor, which significantly enhanced the osteogenic differentiation of mBMSCs in vitro, and bone density and number of trabecular bones in vivo compared with unoptimized O-Exos. Our results indicated that the ASC-exosome-based therapy brings new possibilities for osteoporosis treatment. Besides, engineered exosomes based on transfection of miRNA are a promising strategy to optimize the therapeutic effect of exosomes on osteoporosis.

Keywords

osteoporosisadipose-derived mesenchymal stem cellsexosomesmicroRNAosteogenic differentiation

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Nano Research
Volume 15 Issue 10,
October 2022
Pages 9135-9148
DOI: 10.1007/s12274-022-4554-5
Cite this article:
Sheng C, Guo X, Wan Z, et al. Exosomes derived from human adipose-derived stem cells ameliorate osteoporosis through miR-335-3p/Aplnr axis. Nano Research, 2022, 15(10): 9135-9148. https://doi.org/10.1007/s12274-022-4554-5
Topics:
Drug therapyNanobiotechnology

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Received: 13 April 2022
Revised: 14 May 2022
Accepted: 16 May 2022
Published: 15 July 2022
© Tsinghua University Press 2022
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