Amino acid metabolism in the inflammatory niche
File(s)
Author(s)
Wang, Alice Chun-Yin
Type
Thesis
Abstract
Stroma and parenchyma represent the supportive and functional components in every organ of the body, respectively. Beyond their ability to produce structural support and to differentiate into tissues of mesodermal origin, mesenchymal stromal cells (MSC) exhibit potent immunomodulatory properties. Such a function requires an activation step (‘licensing signal’) provided by the inflammatory microenvironment to which MSC are exposed. My results have attributed immunosuppressive effects of MSC to essential amino acid (EAA) deprivation. Amongst the EAA consuming enzymes examined, blocking nitric oxide synthase 2 (NOS2) and histidine decarboxylase (HDC) both resulted in impaired anti-proliferative activity of MSC, while NOS2 appeared to be a more prominent effector. My results have also demonstrated that TNF-α and IFN-γ differently account for NOS2 and HDC up-regulation, respectively. Furthermore, MyD88 and NF-ĸB were identified as upstream mediators for initiating NOS2 production. The role of TNF-α and NOS2 in MSC-mediated immunosuppression was assessed in vivo using a murine model of peritonitis. MSC treatment remarkably reduced the local inflammatory response during acute peritoneal inflammation. Nevertheless, both Nos2-/- and Tnfr1/r2-/- MSC delivered similar effects compared to WT MSC, indicating the presence of other complementary mechanisms in MSC-mediated immunosuppression in vivo. In addition to their immunomodulatory properties, MSC are fundamental in regulating self-renewal and differentiation of haematopoietic stem cells (HSC). MSC protect HSC from potential damage by maintaining their quiescence. My results have revealed that the ability of MSC to enhance the quiescence of HSC was associated with cell-cycle arrest induced by NOS2. As striking parallels exist between the normal and malignant stem cell niche, I investigated the ability of MSC to protect haematopoietic malignant cells from chemotherapy-induced apoptosis. MSC were observed to confer protection from etoposide-induced necrosis of EL4 cells, possibly due to their ability to suppress EL4 proliferation. Collectively, my results have demonstrated the role of MSC across the fields of immunomodulation, niche-supporting and anti-apoptotic effects.
Version
Open Access
Date Issued
2015-03
Date Awarded
2015-07
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Dazzi, Francesco
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)