Human umbilical cord mesenchymal stromal cell-derived extracellular vesicles alleviate radiation induced pulmonary fibrosis

Abstract

Pulmonary fibrosis, a chronic, fatal lung disease affecting millions worldwide, urgently needs more effective treatments. This article comments on the study by Wang et al, which proposed that human umbilical cord mesenchymal stromal cell-derived exosomes alleviate rats radiation induced pulmonary fibrosis. The study demonstrated that these exosomes suppressed inflammation, extracellular matrix deposition, and epithelial-mesenchymal transition by inhibition of AKT signaling in radiation-exposed alveolar epithelial cells. Despite these observations, aspects of the study merit further discussion. Most importantly, further confirmation is needed to prove that the therapeutic effect is exerted through the AKT signaling pathway. Moreover, the definitions of both mesenchymal stem cell and exosomes require further refinement, more rigorous terms should be mesenchymal stromal cell and extracellular vesicles. It seems apparent that this therapy will develop into one of great clinical value.

Key Words: Human umbilical cord mesenchymal stromal cells; Exosomes; Extracellular vesicles; Pulmonary fibrosis; Inflammation

Core Tip: This commentary examines the study by Wang et al on the role of human umbilical cord mesenchymal stromal cell-derived exosomes in alleviating radiation induced pulmonary fibrosis. However, some issues are worth discussing. First, regarding the definitions of mesenchymal stromal cells and exosomes, according to the latest standards, mesenchymal stromal cell should represent mesenchymal stromal cell, and the so-called exosomes should be extracellular vesicles. Secondly, there are some imprecise or incorrect parts in the text that need to be clarified, especially the evidence for the AKT signaling pathway may be insufficient. Thirdly, this article more systematically discusses the current progress of extracellular vesicles in the treatment of pulmonary fibrosis.

TO THE EDITOR

Interestingly, the article by Wang et al[1] reports that treatment with human umbilical cord mesenchymal stromal cell (MSC)-derived exosomes alleviate radiation induced pulmonary fibrosis (RIPF) in rats. In their study, exosomes inhibited inflammatory factor secretion, extracellular matrix (ECM) collagen protein, and epithelial-mesenchymal transition (EMT), apparently mediated by inhibition of AKT signaling. This work supplied evidence supporting the use of MSC-exosomes for RIPF. However, several scientific and conceptual questions merit further discussion.

The controversial concept of MSC and exosomes

There has long been debate about distinguishing “mesenchymal stem cells” and “mesenchymal stromal cells”. Until recently, they were practically undistinguishable by commonly used identification markers, until a single-cell transcriptomic analysis in 2025 resolved the differences[2]. The new standard for MSC identification, officially released by the International Society for Cell & Gene Therapy at the 2025 annual conference, finally ended the long-standing controversy over the identification of MSC[3]. The name has also been clarified, and MSC are formally defined as “mesenchymal stromal cells”.

Due to their potential for widespread application, exosome biology and application have been studied by multiple groups but remain controversial. For the past decade, the International Association for Vesicle Research has been striving to establish standards and advance their study and use[4]. In 2024, the association issued guidelines to clarify exosome definition[5]. Academically, extracellular vesicles (EVs) are divided into exosomes and ectosomes. The difference between them arises from the mechanism of vesicle formation. However, due to limited isolation methods, these two types of vesicles cannot be completely separated. Therefore, the standard name of exosomes isolated by centrifugation should be EVs. With this definition, the MSC-derived exosomes evaluated by Wang et al[1] strictly should be termed human umbilical cord MSC-EVs (hUCMSC-EVs). We favor this term to provide clarity and unity of concepts, facilitating robust scientific discoveries and advancing the field.

MSC-based therapies for pulmonary fibrosis

Pulmonary fibrosis (PF) is a chronic, progressive, and deadly lung disease in which the accumulation of fibroblasts and ECM induces the destruction of normal alveolar structures, ultimately leading to respiratory failure. Few pharmacological therapies are available, and to date, lung transplantation remains the only possible treatment for patients suffering from end-stage PF. However, the complexity of transplantation surgery and the paucity of donors greatly restrict the application of this treatment. Therefore, there is a pressing need for alternative therapeutic therapies for this complex disease.

MSC and their derivatives are promising therapeutic agents for treating pulmonary disease, and numerous publications support their therapeutic efficacy in PF[6-8]. MSC can be derived from many tissues, including bone marrow, umbilical cord, fat, dental pulp, and even the differentiation of pluripotent stem cells. Their main roles are tissue repair and inflammation regulation, making them useful for skin repair, nervous system illnesses, and PF[9,10]. Different sources have different omics features and may have different functions and signaling interactions[11]. Therefore, it is important to clearly identify the sources from which they are derived. Engineered MSC have been fabricated[12], such as bioconjugation of MSC and type I collagenase[13], CD38 antigen receptor[14] or AuPtCoPS[15], aimed at treating PF.

Based on the effect of MSC, MSC-derived conditioned medium has been evaluated in animal models and human clinical trials. The clinical trials showed that the administration to humans of acute doses is safe and well-tolerated, and MSC-derived conditioned medium appears effective in regenerative medicine, as well as in PF[11,16]. Beyond that, MSC-EVs are now recognized as a novel candidate for cell-free treatment of PF[17]. MSC-EVs attenuated radiation-induced lung vascular damage, inflammation, and fibrosis via miR-214-3p[18] in the radiation-induced injury of endothelial cells, miR-99a[19] and miR-148-3p[20] in the lung of a mice silicosis model. A recent review summarized the state of the field regarding anti-fibrotic and anti-inflammatory pathways elicited in immune cells, alveolar epithelial cells, and myofibroblasts by MSC-miRNAs[21]. Moreover, modulation of monocyte-macrophage migration also affects PF[22]. Methods have been developed to directly exploit both macrophages derived from pluripotent stem cells and macrophage-derived exosomes to repair fibrotic lung tissue[23].

Mechanistic insights into AKT signaling

This study evaluated AKT/nuclear factor-kappa B signaling inhibition in hUCMSC-EVs in vivo and in vitro by western blotting and immunohistochemistry. Because of the multiple functions of AKT signaling, including cell survival, proliferation, and metabolism, whether hUCMSC-EVs mitigate the RIPF process via signaling requires evidence. It is not clear how this signaling pathway relates to suppression of inflammation, collagen deposition, and EMT mentioned earlier in the article. The mechanism can be better explained by loss-of-function and gain-of-function experiments to prove the specific function of the changes mediated by the signaling pathway. Yang et al[24] found that the endoplasmic reticulum stress responder C/EBP homologous protein regulates MSC differentiation into myofibroblasts through transforming growth factor (TGF)/Smad signaling to affect PF. In the same way, adipose-derived MSC supernatant is able to suppress the TGF-β1/Smad signaling pathway to inhibit TGF-β1-induced fibroblast activation[11]. An additional study found that EVs arising from immunity and matrix regulatory cells that were derived from human embryonic stem cells inhibited EMT induced by TGF-β, and different pathways may be affected by immunity and matrix regulatory cell-EVs administered via intratracheal or intravenous routes[25]. In addition, MSC-EVs also attenuated PF by downregulating ATM/P53/P21 signaling[18], β-catenin signaling[20] or the extracellular signal-regulated kinase 1/2 signaling pathway[22]. Perhaps AKT signaling also affects EMT, thereby reducing the degree of fibrosis, given that fibroblasts are major cells responsible for fibrosis and major secretors of ECM proteins. Confirming the role of the AKT signaling pathway is the next step in unraveling the fibrotic regulatory signaling network.

Strengths and limitations

The study demonstrated the impact of hUCMSC-EVs in improving RIPF and proposed that the AKT signaling pathway regulates the effect. The results of this study are basically consistent with previous reports and enrich the research in this field. However, some omissions deserve discussion. There are many similar studies, and the purpose and significance of this study are not very clear. The article cited a few studies before 2021, but there are some two dozen publications from the last three years. In the methods for “Isolation and identification of MSCs”, human ethics materials should be provided. The article reports “α-smooth muscle actin and collagen type 1 alpha 1 as key ECM components”. This statement is not rigorous because α-smooth muscle actin is not a component of the ECM, but an intracellular skeletal protein, which serves as a marker of myofibroblasts or activated mesenchymal cells. In addition, aspects of the writing are inconsistent, such as the term collagen type 1 alpha 1.

CONCLUSION

The article explores the use of hUCMSC-EVs to treat RIPF and presents a novel signaling pathway. However, the function is regulated by that signaling pathway and whether that signaling is the mechanism by which the treatment acts is not fully proven, resulting in a diminished value of the study, including as a reference for future clinical applications. Increasing evidence has proven the efficacy and safety of hUCMSC-EVs, and future investigations may focus on improving and strengthening their function and advancing clinical applications.

ACKNOWLEDGEMENTS

We thank the reviewers for their comments that helped to improve the manuscript.