A non-invasive strategy for suppressing asthmatic airway inflammation and remodeling: Inhalation of nebulized hypoxic hUCMSC-derived extracellular vesicles

Xiaowei Xu; Ying Wang; Xinkai Luo; Xuerong Gao; Weifeng Gu; Yongbin Ma; Lili Xu; Mengzhu Yu; Xi Liu; Jiameng Liu; Xuefeng Wang; Tingting Zheng; Chaoming Mao; Liyang Dong

doi:10.3389/fimmu.2023.1150971

A non-invasive strategy for suppressing asthmatic airway inflammation and remodeling: Inhalation of nebulized hypoxic hUCMSC-derived extracellular vesicles

Front Immunol. 2023 Apr 5:14:1150971. doi: 10.3389/fimmu.2023.1150971. eCollection 2023.

Authors

Xiaowei Xu¹, Ying Wang², Xinkai Luo¹, Xuerong Gao¹, Weifeng Gu¹, Yongbin Ma³, Lili Xu⁴, Mengzhu Yu⁵, Xi Liu⁶, Jiameng Liu¹, Xuefeng Wang^{1

6}, Tingting Zheng¹, Chaoming Mao¹, Liyang Dong¹

Affiliations

¹ Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
² Department of Respiratory Diseases, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China.
³ Department of Central Laboratory, Jintan Hospital of Jiangsu University, Changzhou, Jiangsu, China.
⁴ Department of Respiratory Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
⁵ Department of Paidology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
⁶ Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.

Abstract

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are extremely promising nanoscale cell-free therapeutic agents. We previously identified that intravenous administration (IV) of human umbilical cord MSC-EVs (hUCMSC-EVs), especially hypoxic hUCMSC-EVs (Hypo-EVs), could suppress allergic airway inflammation and remodeling. Here, we further investigated the therapeutic effects of Hypo-EVs administration by atomizing inhalation (INH), which is a non-invasive and efficient drug delivery method for lung diseases. We found that nebulized Hypo-EVs produced by the atomization system (medical/household air compressor and nebulizer) maintained excellent structural integrity. Nebulized Dir-labeled Hypo-EVs inhaled by mice were mainly restricted to lungs. INH administration of Hypo-EVs significantly reduced the airway inflammatory infiltration, decreased the levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF), declined the content of OVA-specific IgE in serum, attenuated the goblet cell metaplasia, and the expressions of subepithelial collagen-1 and α-smooth muscle actin (α-SMA). Notably, Hypo-EV INH administration was generally more potent than Hypo-EV IV in suppressing IL-13 levels and collagen-1 and α-SMA expressions. RNA sequencing revealed that various biological processes, such as cell adhesion, innate immune response, B cell activation, and extracellular space, were associated with the activity of Hypo-EV INH against asthma mice. In addition, Hypo-EVs could load exogenous miR-146a-5p (miR-146a-5p-EVs). Furthermore, INH administration of miR-146a-5p-EVs resulted in a significantly increased expression of miR-146a-5p mostly in lungs, and offered greater protection against the OVA-induced increase in airway inflammation, subepithelial collagen accumulation and myofibroblast compared with nebulized Hypo-EVs. Overall, nebulized Hypo-EVs effectively attenuated allergic airway inflammation and remodeling, potentially creating a non-invasive route for the use of MSC-EVs in asthma treatment.

Keywords: asthma; extracellular vesicles; inhalation device; lung injury; mesenchymal stem cells; nebulized administration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Asthma*
Collagen / metabolism
Collagen Type I
Extracellular Vesicles* / metabolism
Humans
Hypoxia
Inflammation / therapy
Interleukin-13
Mice
MicroRNAs* / genetics
MicroRNAs* / therapeutic use

Substances

Interleukin-13
Collagen Type I
Collagen
MicroRNAs

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (81900562), and key research and development plan of Zhenjiang city (SH2021050).