Ebrahim Nesrine, Al Saihati Hajir A, Alali Zahraa, Mahmoud Sabry Younis Mohamed, Rabaan Ali A, Dessouky Arigue A, Salim Rabab F, Shamaa Ashraf A, Abdallah Ahmed N, Elsherbiny Nehal M, Othman Gamal, Badawy Abdelnaser A, Di Leva Gianpiero, Badr Omnia A
Department of Medical Histology and Cell Biology Faculty of Medicine, Benha University, Benha, Egypt.
Stem Cell Unit, Faculty of Medicine, Benha University, Benha, Egypt.
Stem Cell Res Ther. 2025 May 15;16(1):244. doi: 10.1186/s13287-025-04284-8.
The JAK/STAT signaling pathway plays a crucial role in the release of interferons (IFNs) and the proinflammatory response during SARS-CoV-2 infection, contributing to the cytokine storm characteristic of severe COVID-19 cases. STAT3, a key protein in this pathway, has been implicated in promoting inflammation, making its inhibition a potential therapeutic strategy to mitigate disease severity. Mesenchymal Stem Cell-derived Extracellular Vesicles (MSC-EVs), enriched with immunomodulatory and antiviral miRNAs, offer a promising therapeutic approach by modulating gene expression and regulating inflammatory responses. This study investigates the ability of Lyophilized MSC-EVs to inhibit the JAK/STAT pathway, highlighting their potential application in COVID-19 management.
Male Syrian hamsters were used as an experimental model, housed under controlled laboratory conditions. SARS-CoV-2 (hCoV-19/Egypt/NRC-03/2020) was propagated in Vero E6 cells, and viral titers were determined using plaque assays. Hamsters were intranasally challenged with the virus and treated intraperitoneally with 0.5 mL of lyophilized human Wharton's jelly-derived MSC-extracellular vesicles (MSC-EVs). Histopathological evaluations were performed on lung tissues using H&E, Masson's trichrome, and immunohistochemical staining. Morphometric analyses were conducted to assess lung injury and fibrosis. Western blotting was employed to evaluate protein expression. All procedures adhered to ethical and biosafety guidelines.
The administration of MSC-EVs significantly upregulated the expression levels of miRNA-146a, miRNA-124, miRNA-155, miRNA-29b, miRNA-7, miRNA-145 and miRNA-18a compared to their levels in the COVID-19 group, suggesting a targeted release of miRNA-cargo from the MSC-EVs into the lung tissue of the animals. MSC-EVs impaired the activation of the STAT3/STAT1 signaling pathway and reduced the cytokine storm and coagulopathy associated with COVID-19.
These findings suggest that MSC-EVs have the potential to effectively mitigate the pathogenesis of COVID-19 by targeting the JAK/STAT signaling pathway. Further research is needed to fully understand the mechanisms underlying the therapeutic effects of MSC-EVs and their clinical application in combating the COVID-19 pandemic.
JAK/STAT信号通路在严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染期间干扰素（IFN）的释放和促炎反应中起关键作用，这导致了重症新型冠状病毒肺炎（COVID-19）病例的细胞因子风暴。STAT3是该通路中的一种关键蛋白，与促进炎症有关，抑制它可能是减轻疾病严重程度的一种潜在治疗策略。间充质干细胞衍生的细胞外囊泡（MSC-EV）富含免疫调节和抗病毒微小RNA（miRNA），通过调节基因表达和控制炎症反应提供了一种有前景的治疗方法。本研究调查了冻干的MSC-EV抑制JAK/STAT通路的能力，突出了它们在COVID-19治疗中的潜在应用。
以雄性叙利亚仓鼠作为实验模型，饲养在可控的实验室条件下。SARS-CoV-2（hCoV-19/埃及/NRC-03/2020）在非洲绿猴肾细胞（Vero E6）中繁殖，并使用空斑试验测定病毒滴度。仓鼠经鼻用该病毒攻击，并经腹腔注射0.5 mL冻干的人脐带华通氏胶衍生的MSC-细胞外囊泡（MSC-EV）。使用苏木精-伊红染色（H&E）、马松三色染色和免疫组化染色对肺组织进行组织病理学评估。进行形态计量分析以评估肺损伤和纤维化。采用蛋白质免疫印迹法评估蛋白表达。所有程序均遵循伦理和生物安全指南。
与COVID-19组相比，MSC-EV的给药显著上调了miRNA-146a、miRNA-124、miRNA-155、miRNA-29b、miRNA-7、miRNA-145和miRNA-18a的表达水平，表明miRNA负载从MSC-EV靶向释放到动物的肺组织中。MSC-EV损害了STAT3/STAT1信号通路的激活，并减少了与COVID-19相关的细胞因子风暴和凝血病。
这些发现表明，MSC-EV有可能通过靶向JAK/STAT信号通路有效减轻COVID-19的发病机制。需要进一步研究以充分了解MSC-EV治疗效果的潜在机制及其在抗击COVID-19大流行中的临床应用。
