Microvesicles derived from mesenchymal stem cells: A promising therapeutic strategy for acute respiratory distress syndrome-related pulmonary fibrosis?

Abstract

Pulmonary fibrosis significantly contributes to the pathogenesis of acute respiratory distress syndrome (ARDS), markedly increasing patient mortality. Despite the established anti-fibrotic effects of mesenchymal stem cells (MSCs), numerous challenges hinder their clinical application. A recent study demonstrated that microvesicles (MVs) from MSCs (MSC-MVs) could attenuate ARDS-related pulmonary fibrosis and enhance lung function via hepatocyte growth factor mRNA transcription. This discovery presents a promising strategy for managing ARDS-associated pulmonary fibrosis. This article initially examines the safety and efficacy of MSCs from both basic science and clinical perspectives, subsequently exploring the potential and obstacles of employing MSC-MVs as a novel therapeutic approach. Additionally, it provides perspectives on future research into the application of MSC-MVs in ARDS-associated pulmonary fibrosis.

Key Words: Microvesicles derived from mesenchymal stem cells; Acute respiratory distress syndrome; Pulmonary fibrosis; Hepatocyte growth factor; Mesenchymal stromal cells

Core Tip: Pulmonary fibrosis serves as a critical predictor of adverse outcomes in patients with acute respiratory distress syndrome. Currently, effective treatments for pulmonary fibrosis are notably scarce in clinical settings, highlighting the need for the identification of safe and effective therapeutic strategies. This study supports the Chen et al’s conclusion. To deepen our understanding of this novel therapeutic option, we initially review the safety and efficacy of mesenchymal stem cells therapy. Subsequently, we elaborate on the potential applications and challenges associated with mesenchymal stem cells-microvesicles as an emerging therapeutic modality.

TO THE EDITOR

We concur with the authors’ findings that intravenously administered mesenchymal stem cells (MSCs)-microvesicles (MVs) home to lung injury sites and inhibit acute respiratory distress syndrome (ARDS)-related pulmonary fibrosis. Furthermore, the transfer of hepatocyte growth factor (HGF) mRNA is identified as a crucial mechanism through which MSC-MVs mitigate ARDS-related pulmonary fibrosis. We express our appreciation to the authors for their commitment to elucidating the role of MSC-MVs in treating ARDS-associated pulmonary fibrosis. Their research has uncovered valuable pathways for developing clinical interventions to treat this condition.

OVERVIEW OF MSCs IN LUNG DISEASES

MSCs are unique cell types that play crucial roles in immune regulation, tissue regeneration, and differentiation. Their therapeutic potential has garnered increasing attention from researchers over the past decade. Numerous studies have demonstrated the significant role of MSCs in various diseases, particularly pulmonary disorders. In an animal model of lipopolysaccharide-induced ARDS, tail vein injection of MSCs was observed to up-regulate regulatory T, down-regulate T helper type 17, and decrease inflammatory cytokines in bronchoalveolar lavage fluid and plasma. MSC transplantation markedly improved symptoms and lung function in ARDS[1]. Additionally, MSCs reduced oxidative stress levels in ARDS mice, down-regulated apoptosis-related factors, diminished interstitial lung edema, and repaired damaged alveolar structures[2]. In a bleomycin-induced pulmonary fibrosis mouse model, intratracheal instillation of gingival-derived MSCs decreased neutrophil infiltration and collagen fiber deposition in lung tissues, thereby reducing the extent of pulmonary fibrosis[3]. Furthermore, MSCs have shown remarkable progress in the clinical application for lung diseases. Several preclinical studies have reported significant therapeutic effects of multiple systemic or endotracheal MSC administrations on various respiratory inflammation diseases[4,5]. At the same time, a phase II clinical study involving 66 infants aged 23-28 weeks has demonstrated the safety of bone marrow MSCs in the treatment of bronchopulmonary dysplasia[6]. In the context of idiopathic pulmonary fibrosis, bone marrow-derived MSCs (BMSCs) have been shown to reduce fibrosis by inhibiting the proliferation and differentiation of fibroblasts, thereby decelerating disease progression[7]. Moreover, preliminary clinical trials have highlighted the potential efficacy and safety of allogeneic umbilical cord-derived MSCs (UC-MSCs) in treating chronic obstructive pulmonary disease[8]. In one study, 20 patients with a history of smoking underwent cell-based therapy. Six months post-treatment with UC-MSCs, a notable decrease in the frequency of pulmonary exacerbations and a significant improvement in chronic obstructive pulmonary disease assessment test scores were observed. Additionally, three months after administration, improvements were recorded in mean FEV1/FVC ratios and St George’s Respiratory Questionnaire scores in a subsequent experiment involving UC-MSCs[9]. These findings substantiate the potential utility of BMSCs in managing ARDS-associated pulmonary fibrosis.

MSC-MVs AS A PROMISING THERAPEUTIC STRATEGY FOR FIBROSIS ASSOCIATED WITH ARDS

MSCs are known to exert therapeutic effects through paracrine mechanisms, largely attributed to the release of MVs that facilitate the horizontal transfer of microRNAs, mRNAs, and proteins. MVs, as a critical component of paracrine signaling, play a pivotal role in intercellular communication due to their substantial mRNA content. Consequently, MVs have become a significant focus of research to elucidate the mechanisms of MSC action[10]. MVs originate from the cell membrane following cell activation, injury, or apoptosis and contain bioactive molecules or dense bodies with low electron density, which enable the transport of substances and signal transmission between cells, eliciting a range of biological effects[11]. Studies have shown that MSC-MVs can home to inflammatory sites similarly to their parent cells and transfer bioactive molecules, thereby promoting growth, angiogenesis, anti-apoptosis, anti-oxidation, metabolism, and immunoregulatory properties in injured tissues[12]. Some investigations have demonstrated that MSC-MVs significantly reduce pulmonary edema in ARDS models, control lung inflammation, and decrease mortality in mice[13,14]. In vitro, Hu et al[15] revealed that MSC-MVs restored protein permeability across injured human lung microvascular endothelial cells partly by enhancing angiopoietin-1 secretion. Furthermore, they observed a significant increase in sphingosine-1-phosphate kinase 1 mRNA levels, suggesting a role for sphingosine-1-phosphate signaling in restoring endothelial permeability mediated by MSC-MVs[15]. It is crucial to note that while these cell products offer numerous advantages, they can pose safety risks. For instance, excessive administration of BMSCs (1.5 × 10⁵ cells/mouse or 0.5 × 10⁶ cells/kg) can lead to pulmonary embolism and even mortality[16]. Notably, the optimal dosage of MVs has been determined in a mouse arthritis model, providing a basis for further research on ARDS-related pulmonary fibrosis[17].

HGF is recognized as a significant antifibrotic factor. In an ARDS animal model, HGF substantially inhibited lung fibrous tissue proliferation in a dose-dependent manner, reduced hydroxyproline levels in lung tissues, and reversed pulmonary fibrosis[18]. Previous studies have indicated that MSC-MVs inhibit the proliferation of pulmonary vascular endothelial fibrous tissue via HGF, thereby maintaining pulmonary vascular endothelial barrier function[19]. Consequently, HGF may play a crucial role in the inhibition of pulmonary fibrosis by MSC-MVs. Cellular experiments have confirmed that MSC-MVs mitigate pulmonary vascular endothelial injury and inhibit the development of pulmonary fibrosis through the transfer of HGF mRNA[20]. Notably, in a mouse model of radiation-induced lung injury, Lei et al[21] observed that both MSC-MVs and MSCs expressed a substantial amount of HGF mRNA following intrapulmonary injection, leading to comparable reductions in pulmonary inflammation and fibrosis. Concerning the antifibrotic mechanism of MSC-MVs, some in vivo studies suggest that MSC-MVs may accomplish this by blocking miR-155-mediated pro-fibrotic signaling and releasing HGF in direct contact with other cells, although further research is needed to clarify this mechanism[22]. Importantly, Chen et al[23] reported that MSC-MVs inhibited lung tissue fibrosis and apoptosis, as well as phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin pathway activation, in a rat model of bleomycin-induced lung injury. The therapeutic effects of MSC-MVs appear to be mediated initially by HGF mRNA, followed by HGF protein expression, and are associated with the regulation of autophagy[23]. These findings suggest that MSC-MVs could represent a promising therapeutic strategy against ARDS-related fibrosis.

Currently, 13 clinical trials are registered that employ MSC therapy for patients with ARDS. Despite their early stages and relatively small sample sizes, these trials have effectively evaluated the safety of MSC administration and the efficacy of the treatment in improving clinical outcomes. These outcomes include hemodynamics, inflammation, and both respiratory and systemic parameters. While MSC-MVs were not included in these registered clinical trials, their clinical application in other areas has been preliminarily explored[24,25]. Undoubtedly, these studies will provide a reference for the potential use of MSC-MVs in the clinical treatment of ARDS-related pulmonary fibrosis.

CONCLUSION

ARDS ranks among the three most prevalent pneumonia-related diseases in infants and adults, exerting significant pressure on global healthcare and public health systems. MSCs exhibit promising antifibrotic effects; however, their clinical use is constrained by potential carcinogenicity and ethical concerns. In contrast, MSC-MVs are readily producible in mass, storable, and devoid of immunogenicity and ethical issues. While the study by Chen et al[20] provides valuable insights into potential therapeutic strategies for ARDS-associated pulmonary fibrosis, several aspects require further investigation: (1) The study confirms the mechanism by which MSC-MVs inhibit ARDS-related pulmonary fibrosis, yet the specific targets and regulatory mechanisms remain undefined; (2) Beyond the limitations noted, validation of MSC-MVs’ mechanisms in additional models is necessary; (3) Changes in specific proteins are highly transient; observations made during experimental phases might not accurately represent their behavior throughout disease progression; and (4) Rigorous preclinical studies, meticulously designed clinical trials, and advances in biotechnological methods are imperative to harness the therapeutic potential of MSC-MVs.

ACKNOWLEDGEMENTS

We would like to thank all the members of Tianjin Association of Integrated Traditional Chinese and Western Medicine Ophthalmology for their valuable advice and help.