Lung microenvironment plays a key role on the protective vs. detrimental effects of mesenchymal stromal cell therapy in acute lung injury

Acute respiratory distress syndrome (ARDS) is a complex disorder with high mortality. Most ARDS non-survivors present complications of pulmonary fibrosis. Mesenchymal stromal cells (MSC) are considered good candidates for therapy due to their ability to home into injury sites and help in recovery. However, MSC are sensitive to stimulations from their surroundings and some evidence suggests that MSCs can contribute to fibrosis. Thus it is important to understand how MSCs behave in various lung injury conditions. We used mouse models of acute lung injury to investigate the effects of the injured lung microenvironment in modulating the outcome of MSC administration. Three types of acute lung injury models were used; 1) Hydrochloric acid instillation, as a model for direct chemical injury; 2) Mechanical ventilation, as a model for biophysical injury; 3) Combination of HCl and ventilation in a two hit model. Mouse bone marrow-derived MSCs were separately delivered at different phases of injury in these models. MSC delivery at the onset of mechanical ventilation was able to supress lung injury and fibrosis, while MSC delivery at the proliferative phase of HCl and the two-hit models aggravated injury and fibrosis. MSC delivery at stable reparative phase of injury in these models tended to favour recovery. Analysis of lung microenvironment profiles at the time of MSC delivery indicated that inflammatory and fibrotic mediator upregulation with simultaneous depletion in protective antioxidants correlated with the observed detrimental effects of MSC. Correction of the HCl injured microenvironment by overexpression of antioxidant enzyme before MSC delivery resulted in suppression of lung injury and pulmonary fibrosis after MSC delivery. Modification of MSCs to overexpress antinflammatory and antifibrotic factors reduced inflammatory and fibrotic mediators in the microenvironment and suppressed lung injury and fibrosis in the HCl model. These results indicate a correlation between microenvironment mediator profiles and the outcome of MSC delivery. Furthermore, plasma samples from ARDS patients suggest these microenvironment profiles may also exist within patient cohorts. Thus it is essential to understand microenviroment and MSC interactions and access mediator profiles before MSC delivery in clinical setting.

Department dc:contributor.department

Medical Science

Year dc:date.issued

2017

Author dc:creator

• Islam, Diana

Advisor dc:contributor.advisor

• Zhang, Haibo

Handle dc:identifier.uri

http://hdl.handle.net/1807/97242

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/97242