Extracellular vesicles derived from human dental mesenchymal stem cells stimulated with low-intensity pulsed ultrasound alleviate inflammation-induced bone loss in a mouse model of periodontitis

Tingwei Zhang; Ziqi Chen; Mengyuan Zhu; Xuan Jing; Xiaohui Xu; Xulei Yuan; Mengjiao Zhou; Yanan Zhang; Miao Lu; Duanjing Chen; Shihan Xu; Jinlin Song

doi:10.1016/j.gendis.2022.06.009

Extracellular vesicles derived from human dental mesenchymal stem cells stimulated with low-intensity pulsed ultrasound alleviate inflammation-induced bone loss in a mouse model of periodontitis

Genes Dis. 2022 Jul 19;10(4):1613-1625. doi: 10.1016/j.gendis.2022.06.009. eCollection 2023 Jul.

Authors

Affiliation

¹ Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory for Oral Biomedical Engineering of Higher Education, and Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China.

Abstract

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have emerged as a new mode of intercellular crosstalk and are responsible for many of the therapeutic effects of MSCs. To promote the application of MSC-EVs, recent studies have focused on the manipulation of MSCs to improve the production of EVs and EV-mediated activities. The current paper details an optimization method using non-invasive low-intensity pulsed ultrasound (LIPUS) as the stimulation for improving oral MSC-EV production and effectiveness. Stem cells from apical papilla (SCAP), a type of oral mesenchymal stem cell, displayed intensity-dependent pro-osteogenic and anti-inflammatory responses to LIPUS without significant cytotoxicity or apoptosis. The stimuli increased the secretion of EVs by promoting the expression of neutral sphingomyelinases in SCAP. In addition, EVs from LIPUS-induced SCAP exhibited stronger efficacy in promoting the osteogenic differentiation and anti-inflammation of periodontal ligament cells in vitro and alleviating oral inflammatory bone loss in vivo. In addition, LIPUS stimulation affected the physical characteristics and miRNA cargo of SCAP-EVs. Further investigations indicated that miR-935 is an important mediator of the pro-osteogenic and anti-inflammatory capabilities of LIPUS-induced SCAP-EVs. Taken together, these findings demonstrate that LIPUS is a simple and effective physical method to optimize SCAP-EV production and efficacy.

Keywords: Extracellular vesicles; Low-intensity pulsed ultrasound; Oral bone loss; Periodontitis; Stem cells from apical papilla.