Mesenchymal stromal (stem) cell therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury

• Published in: The European respiratory journal Vol. 59; no. 1; p. 2004216
• Main Authors: Dos Santos, Claudia C, Amatullah, Hajera, Vaswani, Chirag M, Maron-Gutierrez, Tatiana, Kim, Michael, Mei, Shirley H J, Szaszi, Katalin, Monteiro, Ana Paula T, Varkouhi, Amir K, Herreroz, Raquel, Lorente, Jose Angel, Tsoporis, James N, Gupta, Sahil, Ektesabi, Amin, Kavantzas, Nikolaos, Salpeas, Vasileios, Marshall, John C, Rocco, Patricia R M, Marsden, Philip A, Weiss, Daniel J, Stewart, Duncan J, Hu, Pingzhao, Liles, W Conrad
• Format: Journal Article
• Language: English
• Published: England 01.01.2022
• Subjects: Acute Lung Injury - therapy; Animals; Cell- and Tissue-Based Therapy; Endothelial Cells; Humans; Mice; MicroRNAs - genetics; Sepsis - complications; Sepsis - therapy
• ISSN: 0903-1936; 1399-3003
• DOI: 10.1183/13993003.04216-2020

Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3' untranslated region miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells prevents tumour necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC-conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation When administered , MSC-conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b-deficient mice were resistant to pulmonary inflammation and injury induced by lipopolysaccharide (LPS) instillation. Silencing of Ocln in miR-193b-deficient mice partially recovered the susceptibility to LPS-induced lung injury. inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from acute respiratory distress syndrome patients who died with diffuse alveolar damage.