The Role of Mesenchymal Stem Cells to Enhance Immune Function in a Model of Neonatal Infection

Key Words: Neonates, Infection, Mesenchymal stem cells, Sepsis, Inflammation, Immune system

Neonatal sepsis, defined as life-threatening organ dysfunction resulting from infection, remains a leading cause of death and complications in newborns worldwide. Due to the large burden of disease from sepsis, the World Health Organization (WHO) put out a recent resolution to take specific actions to reduce the burden of sepsis. There have been intense efforts to improve the treatment of sepsis, but death rates remain high and the number of babies developing sepsis continues to increase.

Neonates have underdeveloped immune systems, making them highly susceptible to sepsis. Neutrophils and macrophages are two cells that play an important role in the immune system and multiple deficiencies in their functions have been described in neonates. Despite the known defects in innate immunity, there are no current therapies that successfully improve neonatal immune function and reduce their risk of sepsis and its devastating complications.

In this study, neonatal mice will undergo cecal slurry injection. This is a well characterized model of neonatal sepsis. After sepsis, the mice will be treated with mesenchymal stromal cells, (MSCs), a cell known to enhance immune function. We will study survival, bacterial burden, inflammation and organ injury of the neonatal pups after sepsis and cell injection. In addition, we will comprehensively study the cells of the immune system that fight infection and understand why neonatal immune cells are less effective than adult immune cells. We will use our neonatal model of sepsis to see if MSCs can improve the function of these cells. MSC treatment is a very realistic therapy for the near future. It is currently being trialed not for infection but for lung disease and has shown to be safe for neonates.

This proposal is directly relevant to child health because more and more infants and their families continue to suffer from the devastating consequences of sepsis every day with no advances in treatment. This study will systematically characterize the immune defects seen in neonatal sepsis so that we can target therapies such as with mesenchymal stem cells to enhance immune cell function and improve outcomes for many vulnerable neonates globally.