Mesenchymal Stem/Stromal Cells (MSCs) modulate inflammation in rodent and human sepsis.
CCCF ePoster library. Hogan G. Oct 26, 2015; 117379; P12
Grace Hogan
Grace Hogan
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Abstract
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P12


Topic: Basic/Translational Science


Mesenchymal Stem/Stromal Cells (MSCs) modulate inflammation in rodent and human sepsis.



Grace Hogan

Anesthesia, Keenan Research Centre for Biomedical Science and Critical Illness and Injury Research Centre, St Michael’s Hospital, Toronto, Toronto, Canada

Introduction:

Sepsis is among the most common reasons for admission to ICUs throughout the world, and is the third most common cause of death in the United States. Sepsis is a complex and debilitating syndrome which is characterized by vasoplegic shock (distributive shock), myocardial depression, altered microvascular flow, and a diffuse endothelial injury. Despite intensive research, a disease modifying therapy for sepsis remains elusive and current strategies, including antibiotics, fluids and source control, are purely supportive. As a result, mortality remains high and there is urgent need for an effective treatment(1). Human bone marrow MSCs (hBM-MSCs) have shown considerable promise in pre-clinical studies of sepsis. MSCs modulate the immune response to reduce organ injury, and enhance the clearance of bacteria, in murine and rodent Escherichia coli pneumonia(2,3), and in the isolated human lung(4). The mechanisms by which MSCs exert beneficial effects are complex, and include their ability to modulate macrophage phenotype and function.



Objectives: We wished to determine the therapeutic potential of hBM-MSCs in an Escherichia coli pneumonia model of sepsis in the rat and to examine possible mechanisms of action in vitro.

Methods: Adult male Sprague Dawley rats were anesthetized and received E.coli bacteria intratracheally. In all experiments, the animals were sacrificed at 48 hours post-instillation and physiological markers of inflammation and organ injury were assessed. A series of animals were randomized to intravenous administration 4 hours post-instillation of: (1) vehicle (PBS, 800μl; n=12); or (2) 1x107 hBM-MSCs/kg (n=16). In vitro experiments were carried out in parallel to investigate the role of hBM-MSCs in monocyte chemotaxis and their effect on inflammatory cytokine levels. A series of co-culture experiments were conducted on monocytes isolated from both septic and healthy donors. Monocytes being exposed to 50ng/ml lipopolysaccharide (LPS) for either 1, 18 or 24 hours before MSCs were added in Transwell. 24 hours post-MSC addition, the conditioned media was collected and analyzed.

Results:

hBM-MSCs improved E.coli pneumonia associated acute lung injury. All rats in the cell-treated group survived compared to 25% mortality in the vehicle group. Although the results did not reach significance, there was a trend in support of the hBM-MSC group for improved lung compliance and oxygenation. hBM-MSCs decreased immune cell infiltration in the lung, particularly neutrophil infiltration which is a key hallmark of ARDS. In vitro ELISA analysis showed significantly lower levels of the pro-inflammatory cytokine TNF-α in rats who received hBM-MSCs compared to the non-cell-treated group. In vitro, hBM-MSCs increased monocyte chemotaxis alone, and to a further degree when pre-activated with LPS, an effect which was reduced by inhibition of CCR2 on monocytes. Monocyte co-culture experiments eluded to possible mechanism of action of MSCs. In a monocyte preparation isolated from a patient with sepsis, we saw that MSCs significantly reduced inflammation. While levels of TNF-α were lower overall in a subsequent monocyte preparation from a healthy donor, MSCs again showed some indication of an ability to reduce TNF-α levels in LPS-stimulated monocytes compared to naive monocytes. In this pro-inflammatory environment MSCs significantly increased production of keratinocyte growth factor (KGF), a soluble factor with a role in wound healing.



Conclusion: hBM-MSC therapy demonstrates potential in the treatment of sepsis and ARDS, with an ever increasing body of evidence both in vivo and in vitro. This study identifies a potentially important therapeutic effect of MSCs – monocyte recruitment and modulation of inflammation in the infection injured lung.

References: 1. Hayes M, Curley G and Laffey J., (2012). Mesenchymal stem cells - a promising therapy for Acute Respiratory Distress Syndrome. F1000 Medicine Reports 2012, 4:2
2. Curley GF, Hayes M, Ansari B, et al. Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. Thorax 2012;67(6):496-501.
3. Mei SH, Haitsma JJ, Dos Santos CC, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 2010;182(8):1047-1057.
4. McAuley DF, Curley GF, Hamid UI, et al. Clinical Grade Allogeneic Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation. American Journal of Physiology: Lung, Cellular and Molecular Physiology;In Press.
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