Abstract
Background: 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. Methods: 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. Results: Exposure to Covid-19 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. Supplementary Information: The online version contains supplementary material available at 10.1186/s12931-025-03394-4.