TY - JOUR T1 - Mesenchymal Stromal (stem) Cell (MSC) therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.04216-2020 SP - 2004216 AU - Claudia C. dos Santos AU - Hajera Amatullah AU - Chirag M. Vaswani AU - Tatiana Maron-Gutierrez AU - Michael Kim AU - Shirley H.J. Mei AU - Katalin Szaszi AU - Ana Paula T. Monteiro AU - Amir K. Varkouhi AU - Raquel Herreroz AU - Jose Angel Lorente AU - James N. Tsoporis AU - Sahil Gupta AU - Amin Ektesabi AU - Nikolaos Kavantzas AU - Vasileios Salpeas AU - John C. Marshall AU - Patricia R. M. Rocco AU - Philip A. Marsden AU - Daniel J. Weiss AU - Duncan J. Stewart AU - Pingzhao Hu AU - W. Conrad Liles Y1 - 2021/01/01 UR - http://erj.ersjournals.com/content/early/2021/05/28/13993003.04216-2020.abstract N2 - 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′ UTR miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells (HPMECs) prevents tumor 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 in vitro. When administered in vivo, 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 LPS instillation. Silencing of Ocln in miR-193b deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. dos Santos has nothing to disclose.Conflict of interest: Dr. Amatullah has nothing to disclose.Conflict of interest: Dr. Vaswani has nothing to disclose.Conflict of interest: Dr. Maron-Gutierrez has nothing to disclose.Conflict of interest: Mr. Kim has nothing to disclose.Conflict of interest: Dr. Mei has nothing to disclose.Conflict of interest: Dr. Szaszi has nothing to disclose.Conflict of interest: Dr. Teixeira Monteiro has nothing to disclose.Conflict of interest: Dr. Varkouhi has nothing to disclose.Conflict of interest: Dr. Herrero has nothing to disclose.Conflict of interest: Dr. Lorente has nothing to disclose.Conflict of interest: Dr. Tsoporis has nothing to disclose.Conflict of interest: Dr. Gupta has nothing to disclose.Conflict of interest: Dr. Ektesabi has nothing to disclose.Conflict of interest: Dr. Kavantzas has nothing to disclose.Conflict of interest: Dr. Salpeas has nothing to disclose.Conflict of interest: Dr. Marshall reports personal fees from AM Pharma, personal fees from Gilead Pharmaceuticals, outside the submitted work.Conflict of interest: Dr. Rocco has nothing to disclose.Conflict of interest: Dr. Marsden has nothing to disclose.Conflict of interest: Dr. Weiss has nothing to disclose.Conflict of interest: Dr. Stewart reports other from Northern Therapeutics, outside the submitted work.Conflict of interest: Dr. Hu has nothing to disclose.Conflict of interest: Dr. Liles has nothing to disclose. ER -