Sepsis is a complex and dynamic disease process that is characterized by activation of the innate immune system, and an inflammatory response to a systemic infection. While an exaggerated immune response has been associated with the morbidity and mortality of severe sepsis and septic shock, anti-inflammatory therapies have not resulted in improvements in patient outcome. Thus, it is important to consider other mechanisms of the host immune response that may be contributing to the detrimental consequences of sepsis. During sepsis, part of the pathobiology of the disease is related to abnormal neutrophil function, and a release of immature forms of neutrophils from the bone marrow, which may contribute to an impaired eradication of infecting microorganisms. As mortality remains high, new and innovative strategies are necessary to advance the treatment of sepsis. Due to the intricacies of the immune response during sepsis, alternative strategies have been considered, including cell-based therapies. Recently, the therapeutic effects of mesenchymal stromal cells (MSCs) have been studied in animal models of sepsis. While the initial studies have looked promising, the mechanisms responsible for the beneficial effects of MSCs have not been fully elucidated. In the present application, we hypothesize that stromal-cell derived factor-1 (SDF-1/CXCL12) is a critical mediator of the MSC response during sepsis, and that MSCs will rescue dysfunctional neutrophils in the setting of sepsis, contributing to an improved outcome. To test our hypotheses, we propose three aims.
In Aim 1 we will investigate the importance of SDF-1 for the therapeutic effects of MSCs in an experimental mouse model of sepsis, using cecal ligation and puncture (CLP). Our preliminary data show that treatment with MSCs improves survival and enhances bacterial clearance, and neutrophils are critical for this beneficial response. To test the importance of SDF-1 in MSCs, we will silence SDF-1 and determine whether the protective properties of MSCs are lost in septic animals, compared with wild-type MSCs. Moreover, we will assess the effects of SDF-1 overexpression to improve MSC function.
In Aim 2 we will explore the interaction between MSCs and neutrophils during experimental sepsis in mice, and elucidate the role of MSC-derived SDF-1 to improve neutrophil function. We will investigate the ability of MSCs to promote neutrophil maturation, and to improve migration, phagocytosis and bacterial killing. In addition, we will determine whether MSCs alter neutrophil survival, and promote the resolution of inflammation.
In Aim 3 we will determine whether MSCs can rescue human neutrophil dysfunction in cells harvested from patients with sepsis, and elucidate the role of SDF-1 in this MSC response. We believe that our application will further reveal the potential of MSCs as a therapy for sepsis, and advance our understanding of how MSCs promote a beneficial response during sepsis.

Public Health Relevance

Sepsis is a medical condition caused by an underlying infection that leads to an inflammatory process throughout the body. Although there have been intense efforts to improve the treatment of sepsis, death rates remain high and the number of people developing sepsis continues to increase. In this project we will investigate new approaches for treating sepsis using cells (mesenchymal stromal cells) as a therapy, and discover ways in which these cells enhance immune cell function to eradicate the infection and subsequently resolve the inflammatory response, thus leading to an improved outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM118456-03
Application #
9427994
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2016-05-10
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Ghanta, Sailaja; Tsoyi, Konstantin; Liu, Xiaoli et al. (2017) Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction. Am J Respir Cell Mol Biol 56:300-309
Tsoyi, Konstantin; Hall, Sean R R; Dalli, Jesmond et al. (2016) Carbon Monoxide Improves Efficacy of Mesenchymal Stromal Cells During Sepsis by Production of Specialized Proresolving Lipid Mediators. Crit Care Med 44:e1236-e1245