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
Login now to access Regular content available to all registered users.

You may also access this content "anytime, anywhere" with the Free MULTILEARNING App for iOS and Android
Rate & Comment (0)

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



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.

  1. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A;Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress  Syndrome in Intensive Care Units in 50 Countries.LUNG SAFE Investigators; ESICM Trials Group. JAMA. 2016 Feb 23;315(8):788-800. Erratum in: JAMA. 2016 Jul 19;316(3):350.
  2. Villar J, Blanco J, Anon JM, et al. The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med. 2011; 37(12):1932-1941.
  3. Herridge MS, Tansey CM, Matte A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011; 364(14):1293-1304.
  4. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One; 2010; 5(4):e10088.
  5. Moodley Y, Sturm M, Shaw K, Shimbori C, Tan DB, Kolb M, Graham R. Human mesenchymal stem cells attenuate early damage in a ventilated pig model of acute lung injury. Stem Cell Res. 2016 May 12;17(1):25-31.
  6. Zhang G, Zou X, Huang Y, Wang F, Miao S, Liu G, Chen M, Zhu Y. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect Against Acute Kidney Injury Through Anti-Oxidation by Enhancing Nrf2/ARE Activation in Rats. Kidney Blood Press Res. 2016;41(2):119-28.
  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.
  8. English K, Barry FP, Field-Corbett CP, Mahon BP. IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett; 2007; 110(2):91-100.


    This eLearning portal is powered by:
    This eLearning portal is powered by MULTIEPORTAL
Anonymous User Privacy Preferences

Strictly Necessary Cookies (Always Active)

MULTILEARNING platforms and tools hereinafter referred as “MLG SOFTWARE” are provided to you as pure educational platforms/services requiring cookies to operate. In the case of the MLG SOFTWARE, cookies are essential for the Platform to function properly for the provision of education. If these cookies are disabled, a large subset of the functionality provided by the Platform will either be unavailable or cease to work as expected. The MLG SOFTWARE do not capture non-essential activities such as menu items and listings you click on or pages viewed.

Performance Cookies

Performance cookies are used to analyse how visitors use a website in order to provide a better user experience.

Save Settings