Migrasomes derived from human umbilical cord mesenchymal stem cells: a new therapeutic agent for ovalbumin-induced asthma in mice

Abstract

Background  Asthma is a prevalent respiratory disease, and its management remains largely unsatisfactory. Mesenchymal stem cells (MSCs) have been demonstrated to be efficacious in reducing airway inflammation in experimental allergic diseases, representing a potential alternative treatment for asthma. Migrasomes are recently identified extracellular vesicles (EVs) generated in migrating cells and facilitate intercellular communication. The objective of this study was to investigate the therapeutic effects of migrasomes obtained from MSC in a model of asthma. Methods  Migrasomes produced by human umbilical cord MSCs (hUCMSCs) were isolated by sequential centrifugation. Characterization of hUCMSC-derived migrasomes were carried out by transmission electron microscopy and western blot analysis. The therapeutic effects of migrasomes on airway inflammation in ovalbumin (OVA)-induced asthmatic mice were evaluated by hematoxylin-eosin (HE) and periodic-acid schiff (PAS) staining, and their mechanism were further testified by immunofluorescent staining, real-time PCR and flow cytometry. Results  Here, we showed that inhibition of migrasomes’ production dramatically impaired the anti-inflammatory effects of hUCMSCs in OVA animals, as evidenced by a notable increase in both the infiltration of inflammatory cells and the number of epithelial goblet cells. We successfully isolated hUCMSC-migrasomes, which were morphologically intact and positive for the specific migrasomes markers. The administration of hUCMSC-migrasomes was observed to significantly ameliorate the symptoms of airway inflammation and mucus production in asthmatic mice. Additionally, the expression of Th2 cytokines (IL-4, IL-5 and IL-13) were found to be reduced, while the activation of dendritic cells (DCs) was inhibited. HUCMSC-migrasomes could possibly be delivered to lung region after injection, and were able to be taken in by DCs both in vivo and in vitro. Notably, in vitro, migraosmes decreased the capacity of

1. Introduction

Asthma is the most common chronic inflammatory disease of the lungs, affecting over 350 million people worldwide. This disease is typically associated with repetitive episodes of airway obstruction caused by airway inflammation and excessive production of mucus [1, 2]. Corticosteroids are effective at managing the symptomatic relief, however, 10% of patients do not respond to the treatment, and they are associated with severe long-term side effects [3, 4]. The quest for effective and safe asthma treatment drugs is always on the way for researchers.

With the migration ability (homing to injury tissues) and immunomodulatory attributes, mesenchymal stem cells (MSCs) received significant attention in the treatment of inflammatory diseases [5, 6], and accumulating evidences showed that exogenous MSCs exhibit anti-inflammatory properties in various stabilized asthma murine models [7]. The secreted biological factors are regarded as a key mechanism of action of MSCs [8], therefore, MSC-derived secreted products, mainly conditioned medium (CM) [9–11] or extracellular vesicles (EVs) [12] were widely investigated in pre-clinical intervention of asthma, and showed bright results in these experimental asthma models. In fact, from a clinical standpoint, MSCs-based cell-free products are more promising therapeutic option in asthma, as they bypass the risks of tumorgenicity, immune rejection, and ethical issues in cell therapy [13].

Recently, a novel secreted pattern of migratory cells based on large membrane-bound vesicular structures encapsulating several smaller vesicles (50–100 nm), known as migrasomes, has been described [14]. Migrasomes are generated during cell migration and are randomly distributed inside thin cellular structures called retraction fibers (RFs). When the cells move away, the RFs will break, then the migrasomes will be released and subsequently taken up by the extracellular space cells, as such, migrasomes mediate intercellular communication [15]. Various types of migratory cells, including podocyte cells [16], macrophage [17] and tumor cells [18] can generated migrasomes.