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MESENCHYMAL STROMAL (STEM) CELL THERAPY MODULATES MIR-193B5P EXPRESSION TO ATTENUATE SEPSIS-INDUCED ACUTE LUNG INJURY
Células mesenquimais estromais
Modula expressão de miR-193b-5p
Atenuar a lesão pulmonar aguda
Induzida por sepse
Cell therapy
Modulates miR-193b- 5p expression
Attenuate
Acute lung injury
Sepsis-induced
Author
Santos, Claudia C. dos
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, Ducan J.
Hu, Pingzhao
Liles, W. Conrad
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, Ducan J.
Hu, Pingzhao
Liles, W. Conrad
Affilliation
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Dept of Physiology, Temerty Faculty of Medicine, University of Toronto. Toronto, ON, Canada / Institute of Medical Sciences and Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto.Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Dept of Physiology, Temerty Faculty of Medicine, University of Toronto. Toronto, ON, Canada.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
Regenerative Medicine Program, Ottawa Hospital Research Institute. Ottawa, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Dept of Surgery. University of Toronto, Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
University Hospital of Getafe, Critical Care Dept. Madrid, Spain.
University Hospital of Getafe, Critical Care Dept. Madrid, Spain / Centros de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias. Madrid, Spain / Universidad Europea de Madrid. Madrid, Spain..
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Institute of Medical Sciences and Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto. Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Institute of Medical Sciences and Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto. Toronto, ON, Canada.
1st Dept of Pathology, School of Medicine, National and Kapodistrian, University of Athens. Athens, Greece.
1st Dept of Pathology, School of Medicine, National and Kapodistrian, University of Athens. Athens, Greece.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Institute of Medical Sciences and Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto. Toronto, ON, Canada / Dept of Surgery, University of Toronto. Toronto, ON, Canada.
Universidade Federal do Rio de Janeiro. Instituto de Biofisica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
Dept of Medicine, University of Vermont, Burlington, VT, USA.
Regenerative Medicine Program, Ottawa Hospital Research Institute. Ottawa, ON, Canada.
Dept of Biochemistry and Medical Genetics, University of Manitoba. Winnipeg, MB, Canada.
Dept of Medicine, University of Washington, Seattle, WA, USA.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Dept of Physiology, Temerty Faculty of Medicine, University of Toronto. Toronto, ON, Canada.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
Regenerative Medicine Program, Ottawa Hospital Research Institute. Ottawa, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Dept of Surgery. University of Toronto, Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
University Hospital of Getafe, Critical Care Dept. Madrid, Spain.
University Hospital of Getafe, Critical Care Dept. Madrid, Spain / Centros de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias. Madrid, Spain / Universidad Europea de Madrid. Madrid, Spain..
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Institute of Medical Sciences and Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto. Toronto, ON, Canada.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Institute of Medical Sciences and Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto. Toronto, ON, Canada.
1st Dept of Pathology, School of Medicine, National and Kapodistrian, University of Athens. Athens, Greece.
1st Dept of Pathology, School of Medicine, National and Kapodistrian, University of Athens. Athens, Greece.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada / Institute of Medical Sciences and Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto. Toronto, ON, Canada / Dept of Surgery, University of Toronto. Toronto, ON, Canada.
Universidade Federal do Rio de Janeiro. Instituto de Biofisica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.
The Keenan Research Centre for Biomedical Science of St Michael’s Hospital. Toronto, ON, Canada.
Dept of Medicine, University of Vermont, Burlington, VT, USA.
Regenerative Medicine Program, Ottawa Hospital Research Institute. Ottawa, ON, Canada.
Dept of Biochemistry and Medical Genetics, University of Manitoba. Winnipeg, MB, Canada.
Dept of Medicine, University of Washington, Seattle, WA, USA.
Abstract
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 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
lipopolysaccharide (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.
Keywords in Portuguese
TerapiaCélulas mesenquimais estromais
Modula expressão de miR-193b-5p
Atenuar a lesão pulmonar aguda
Induzida por sepse
Keywords
Mesenchymal stromal (stem)Cell therapy
Modulates miR-193b- 5p expression
Attenuate
Acute lung injury
Sepsis-induced
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