Interleukin-18-primed human umbilical cord-mesenchymal stem cells achieve superior therapeutic efficacy for severe viral pneumonia via enhancing T-cell immunosuppression

Abstract

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. In this study, 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 improve the therapeutic effect of hUC-MSCs in vivo. In vitro, we demonstrated that IL-18-primed hUC-MSCs (IL18-hUCMSC) have higher proliferative ability than non-primed hUC-MSCs (hUCMSCcon). In addition, VCAM-1, MMP-1, TGF-β1, and some chemokines (CCL2 and CXCL12 cytokines) 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). 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.

Unveiling the functional heterogeneity of cytokine-primed human umbilical cord mesenchymal stem cells through single-cell RNA sequencing

“…hUC-MSCs were isolated from UC Wharton’s jelly and cultured according to previously described methods [ 19 ]. These primary cells can be MSCs, including those that undergo tri-lineage differentiation into adipogenic, chondrogenic, and osteogenic cells (Additional file 1: Fig S1 A ).…”

“…It is crucial to study the distinct factors responsible for MSC priming to aid in the treatment of different diseases. Various inflammatory cytokines have been reported to prime MSCs, and their function and therapeutic efficacy have been investigated across different diseases [ 13 – 19 ]. However, our understanding of the disease microenvironment and its impact on MSC activation requires further development.…”

Successful salvage of a severe COVID-19 patient previously with lung cancer and radiation pneumonitis by mesenchymal stem cells: a case report and literature review

“…MSCs inhibited Th17 and induced Treg differentiation, which led to the attenuation of lung injury caused by the virus ( 65 ). On the other hand, when MSCs were injected in mice with viral pneumonia, attenuated proliferation of both CD3 + , CD4 + and CD4 + , CD8 + T cells was observed, resulting in the significant suppression of pro-inflammation factor level and the protection of mice alveolar epithelial cells from inflammatory injury similar to severe COVID-19 ( 66 ).…”

Recent advances in pre-conditioned mesenchymal stem/stromal cell (MSCs) therapy in organ failure; a comprehensive review of preclinical studies

“…Importantly, MnSOD-MSCs differentiated into epithelial-like cells in vivo [ 104 ], indicating the excellent capability of MnSOD-MSCs. Also, Liao et al (2023) have found that administration of IL18-hUC-MSCs could drastically decrease viral load, fibrosis, and cell apoptosis in acute lung injuries [ 105 ]. Notably, T cell exudation and pro-inflammatory cytokine release in bronchoalveolar lavage fluid (BALF) were significantly inhibited by IL18-hUCMSC therapy [ 105 ].…”