Mesenchymal stromal cells reprogram macrophages with processing bodies

Abstract

Background & Aim: Mesenchymal stromal cells (MSCs) are an investigational cell therapy for inflammatory diseases. Although they have robust anti-inflammatory properties, their success has been variable in clinical trials due to an unclear understanding of their mechanism. Once injected, a majority of MSCs traffic to the lung, where they are rapidly cleared, signifying an opportunity to target lung inflammatory [Figure presented] conditions such as acute respiratory distress syndrome (ARDS). ARDS is a catastrophic condition of the lungs, involving pulmonary inflammation that develops with severe SARS-CoV2 and other respiratory infections. MSCs are expected to prevent alveolar damage by suppressing the immune response and there is evidence that MSCs protect in phase I/IIa trials for ARDS associated with COVID-19. While these results are promising, understanding the mechanism is critical to determine dosing, maximize efficacy, and ultimately lead to an approved product. Methods, Results & Conclusion: We and others have demonstrated that within their short time in the lung, MSCs interact with monocytes and macrophages. Through direct cell contact, MSCs transfer cytoplasmic components, notably cytoplasmic processing-bodies (p-bodies) to monocytes and macrophages. P-bodies are membrane-less organelles that contain RNA binding proteins, microRNAs, and mRNAs enriched for genes that regulate the transcriptional landscape of cells. MSC interactions result in long-term transcriptional reprogramming of monocytes and macrophages to suppress a helper T cell response and upregulate tissue repair pathways. To investigate the mechanisms of MSCs in vivo, we utilized 2 mouse models of lung inflammation: 1. intranasal lipopolysaccharide (LPS) to study general acute inflammation and 2. an engineered vesicular stomatitis virus (VSV) with a SARS-CoV2 Spike protein. Using these models, we demonstrated that during inflammation cytoplasm of MSCs transferred to lung macrophages to decrease activation and the expression of MHC-II. Further, MSCs prevented a decrease in resident alveolar macrophages, suppressed proinflammatory macrophages, and blocked an influx in infiltrating monocytes (Fig 1). Depleting p-bodies from MSCs abolished the beneficial effects, despite transfer cytoplasmic component to macrophages at similar levels of control MSCs. Overall, our data suggest a novel form of cell communication that could explain how MSCs could lead to long-term beneficial effects on lung inflammation despite being rapidly cleared. [Figure presented]