Therapeutic Efficacy of Human Umbilical Cord Mesenchymal Stem Cell-derived Extracellular Vesicles in pre-clinical Model of Acute Respiratory Distress Syndrome
CCCF ePoster library. Varkouhi A. Oct 31, 2016; 155980; ORAL
Amir Khashayar Varkouhi
Amir Khashayar Varkouhi
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Topic: Basic or Translational Science

Therapeutic Efficacy of Human Umbilical Cord Mesenchymal Stem Cell-derived Extracellular Vesicles in pre-clinical Model of Acute Respiratory Distress Syndrome


Varkouhi, Amir K1; Ormesher, Lindsay1; Jerkic, Mirjana1, dos Santos, Claudia1,2, Laffey, John1,3 and Curley, Gerard1,3
1Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto
2Department of Critical Care, St. Michael's Hospital, University of Toronto
3Department of Anesthesia, St. Michael’s Hospital, University of Toronto
 

 



Abstract:

Background: Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition, resulting in life threatening acute hypoxic respiratory failure and a 40% risk of death1,2. Over the last decades many novel therapeutics have been evaluated for the treatment of ARDS yet none have proven efficacious, and thus supportive care strategies remain the mainstays of therapy3. Mesenchymal Stem Cells (MSCs) are multi-potent cells with strong immunomodulatory properties that constitute an innovative approach with substantial therapeutic promise for ARDS4,5. MSCs release extracellular vesicles (EVs) containing bioactive molecules, such as proteins, mRNAs, microRNAs and lipids, which mediate the cross-talk between MSCs and immune cells. It was reported that EVs could recapitulate the therapeutic effects of stem cell transplantation6,7. Additionally, priming MSCs with specific inflammatory mediators such as IFNg may improve the immunomodulatory function of these cells and their extracellular vesicles8.
Objectives: The aim of this study was to investigate the therapeutic effects of EVs derived from IFNg-primed and non-primed MSCs in a pre-clinical rat model of ARDS. The effects of EVs on anti-inflammatory and anti-bacterial properties of immune cells was investigated in vitro.
Methods: Extracellular vesicles were isolated from the conditioned medium of primed (IFNg, 50 ng/mL for 8 hours) or non-primed human umbilical cord MSCs by applying a series of centrifugation steps followed by reconstitution of the EV pellets in PBS. The approximate number and size of EVs were characterized by flowcytometry. The in vitro effects of EVs on bacterial phagocytosis/clearance were investigated in a human monocyte cell line (THP1) incubated with EVs for 72 hours. For the animal studies, we induced a pneumonia model of ARDS in male rats by intra-tracheal instillation of E. coli (5x10^9 CFU/kg), 30 minutes pre-treatment. Animals were divided into 3 treatment groups: 1. EVs derived from primed cells (n=11), 2. EVs derived from non-primed cells (n=8) and 3. PBS group (n= 12). Animals in EV treatment groups received a dose of about 75 million EVs/kg via tail vain injection.  The extent of recovery and phenotype of animals in different treatment groups were assessed 48 hours post-treatment.
Results: Incubation of THP1 cells with EVs derived from IFNg-primed MSCs significantly enhanced the bacterial phagocytosis and bacterial clearance properties of these cells by 60% and 40%, respectively. In animal studies, treatment with EVs isolated from both primed and non-primed MSCs significantly enhanced animal survival (from 66.7% in PBS group to 91-100% in EVs treated groups, P<0.05), while arterial blood oxygenation (at FiO2= 1.0) was improved only in animals treated with EVs derived from IFNg-primed MSCs. Additionally, a dramatic increase in the number of macrophages in bronchoalveolar lavage (BAL) fluid of both EV-treated animal groups was observed.
Conclusions: Our results demonstrate that treatment with extracellular vesicles isolated from UC-MSCs can efficiently enhance survival in rats with E. coli induced ARDS. In addition, treatment with EVs derived from IFNg-primed MSCs may enhance their therapeutic effect, by improving the blood oxygenation in ARDS rats. Together with our in vitro findings, it can be concluded that MSC-derived EVs may represent an attractive option for future clinical trials in ARDS.
 


References:
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  7. Monsel A, Zhu YG, Gennai S, Hao Q, Hu S, Rouby JJ, Rosenzwajg M, Matthay MA, Lee JW. Therapeutic Effects of Human Mesenchymal Stem Cell-derived Microvesicles in Severe Pneumonia in Mice. Am J Respir Crit Care Med. 2015 Aug 1;192(3):324-36.
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