Interleukin-18-Primed Human Umbilical Cord-Mesenchymal Stem Cells Achieve Superior Therapeutic Efficacy for Severe Viral Pneumonia Via Enhancing T-Cell Immunosuppression

Background: Coronavirus disease 2019 (COVID-19) treatments are still urgently needed for critically and severely ill patients. Human umbilical cord-mesenchymal stem cells (hUC-MSCs) infusion has therapeutic benefits in COVID-19 patients; however, uncertain therapeutic efficacy has been reported in severe patients. Here, we investigated the effects of IL-18 to prime hUC-MSCs in the treatment of severe pneumonia.Methods: We selected an appropriate cytokine, IL-18, based on the special cytokine expression profile in severe pneumonia of mice induced by H1N1virus to prime hUC-MSCs in vitro, and their related characteristics were analyzed. The weight change, survival rate and lung injuries of mice were evaluated, and the underling molecular mechanisms were investigated in vivo.Findings: In vitro, we demonstrated that IL-18-primed hUC-MSCs (IL18-hUCMSC) have higher proliferative ability than non-primed hUC-MSCs (hUCMSCcon), and there was no significant difference in their migration capacity. In addition, VCAM-1, MMP-1, TGF-β1, and some chemokines (CCL2 and CXCL12, for example) are more highly expressed in IL18-hUCMSCs. We found that IL18-hUCMSC significantly enhanced the immunosuppressive effect on CD3+ T-cells. In vivo, we demonstrated that IL18-hUCMSC infusion could reduce the body weight loss caused by a viral infection and significantly improve the survival rate. Of note, IL18-hUCMSC can also significantly attenuate certain clinical symptoms, including reduced activity, ruffled fur, hunched backs, and lung injuries. Pathologically, IL18-hUCMSC transplantation significantly enhanced the inhibition of inflammation, viral load, fibrosis, and cell apoptosis in acute lung injuries. Notably, IL18-hUCMSC treatment has a superior inhibitory effect on T-cell exudation and proinflammatory cytokine secretion in bronchoalveolar lavage fluid (BALF).Interpretation: Altogether, IL-18 is a promising cytokine that can prime hUC-MSCs to improve the efficacy of precision therapy against viral-induced pneumonia, such as COVID-19.Funding Information: This work was supported by the Key Project of Science and Technology helps economy (2020) for drug development of novel coronavirus pneumonia; and Guangdong Basic and Applied Basic Research Foundation (Grant no. 2021A1515011108).Declaration of Interests: The authors declare that they have no conflict of interest.Ethics Approval Statement: Eight-week-old specific pathogen-free (SPF) grade female BALB/c mice (body weight: 18-20 g) were purchased from the Animal Center at the Medical Laboratory of Guangdong Province, China. All mice were maintained in a specific pathogen-free facility, and all animal procedures and protocols were reviewed and approved by the animal experimental ethics committee of the South China Agricultural University. The studies involving human participants were reviewed and approved by Maternal and Child Health Hospital of Longgang District. The patients/participants provided written informed consent to participate in this study.