Modulation of NEAT1 and MALAT1 expression in WJ-MSCs by Covid-19 serum: a foundation for EVs-mediated therapy

Mesenchymal stem cells (MSCs)-based and MSCs-derived extracellular vesicle (EV) therapies, have garnered significant attention as potential treatments for severe Coronavirus disease 19 (Covid-19), leading to evaluation in numerous clinical trials. This interest stems from the observed ability of MSCs, and their EVs, to mitigate the hyper-inflammatory state that characterizes severe cases of the disease. However, despite the promising preclinical and early clinical results, the precise mechanisms of action remain unclear, hindering therapy optimization. This study investigated the response of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) to a diverse panel of sera collected from multiple hospitalized Covid-19 patients, aiming to recapitulate in vitro the spectrum of inflammatory conditions MSCs encounter in vivo. Exposure to Covid-1 Please provide the full uncropped Gels and Blots image(s) as file type ‘supplementary file’0.9 serum activated WJ-MSCs, increasing proliferation and RNA/protein synthesis. Transcriptomic analysis revealed an early and significant downregulation of the inflammation-related long non-coding RNAs (lncRNAs) NEAT1 and MALAT1. This downregulation of NEAT1 and MALAT1, triggered by Covid-19 serum, suggests a potential mechanism by which WJ-MSCs may limit excessive inflammation. Importantly, reducing MALAT1 (and to a lesser extent NEAT1) expression in WJ-MSCs enhanced the therapeutic potential of MSC-derived EVs. This suggests that targeting pro-inflammatory lncRNAs in parental cells could be a promising therapeutic strategy for managing Covid-19 and other inflammatory lung diseases.