Extracellular vesicles derived from neural EGFL-Like 1-modified mesenchymal stem cells improve acellular bone regeneration via the miR-25-5p-SMAD2 signaling axis

Yanhua Lan; Huizhi Xie; Qianrui Jin; Xiaomin Zhao; Yang Shi; Yanyan Zhou; Zihe Hu; Yi Ye; Xiaoyuan Huang; Yingjia Sun; Zhuo Chen; Zhijian Xie

doi:10.1016/j.bioactmat.2022.01.019

Extracellular vesicles derived from neural EGFL-Like 1-modified mesenchymal stem cells improve acellular bone regeneration via the miR-25-5p-SMAD2 signaling axis

Bioact Mater. 2022 Jan 19:17:457-470. doi: 10.1016/j.bioactmat.2022.01.019. eCollection 2022 Nov.

Authors

Yanhua Lan¹, Huizhi Xie², Qianrui Jin¹, Xiaomin Zhao¹, Yang Shi¹, Yanyan Zhou¹, Zihe Hu¹, Yi Ye¹, Xiaoyuan Huang¹, Yingjia Sun¹, Zhuo Chen¹, Zhijian Xie¹

Affiliations

¹ Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310006, China.
² Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, 999077, China.

Abstract

Stem cell based transplants effectively regenerate tissues; however, limitations such as immune rejection and teratoma formation prevent their application. Extracellular vesicles (EVs)-mediated acellular tissue regeneration is a promising alternative to stem cell based transplants. Although neural EGFL-like 1 (Nell1) is known to contribute to the osteogenic differentiation of bone marrow stem cells (BMSCs), it remains unknown whether EVs are involved in this process. Here, we present that EVs derived from Nell1-modified BMSCs (Nell1/EVs) have a stronger ability to promote BMSC osteogenesis owing to miR-25-5p downregulation. MiR-25-5p inhibits osteogenesis by targeting Smad2 and suppressing the SMAD and extracellular signal-related kinase 1 and 2 (ERK1/2) pathway activation. In addition, we demonstrate that the 3D-Nell1/EV-hydrogel system is beneficial for bone regeneration in vivo, probably stemming from a slow, continuous release and high concentration of EVs in the bone defect area. Thus, our results have shown the potential of Nell1/EVs as a novel acellular bone regeneration strategy. Mechanistically, the identification of miR-25-5p-SMAD2 signaling axis expands the knowledge of Nell1/EVs induced osteogenesis.

Keywords: Bone regeneration; Cell-free scaffolds; Extracellular vesicles; Mesenchymal stem cells; miRNAs.