Tracking the memory of liver injury in bone marrow cells

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global health burden that leads to hepatic complications and cardiovascular risk as a spectrum of metabolic diseases. This thesis aims to investigate the role of myeloid cells in MAFLD with focuses on the immunometabolism and production from bone marrow haematopoietic stem and progenitor cells (HSPCs). In Chapter 3, the effect of modulating the activity of pyruvate kinase M2 (PKM2), a glycolytic enzyme, on myeloid cells was assessed in two diet-induced steatohepatitis mouse models. Systemic pharmacological activation of PKM2 showed therapeutic effect to varying degree in each model, although PKM2 activity in myeloid cells are unlikely to be involved. In the two dietary models, the extent of hepatic immune response was associated with the activation of HSPCs toward myeloid cell generation, suggesting the linking between the liver and the bone marrow. In Chapter 4 and 5, mouse models of transient steatohepatitis with young or old age were compared not only to examine the recovery from steatohepatitis but also to study the long-term impact of temporary metabolic stress. In young mice, although hepatic immune response and activation of HSPCs mostly resolved following transient steatohepatitis, we detected residual hepatic immune response and proliferation in primitive HSPC. In contrast, in aged mice, the liver histology exhibited steatosis with low immune cell infiltrate, and HSPCs were relatively unresponsive to dietary stress. However, transcriptomic analysis showed that hepatic immune response remained upregulated almost similarly between transient and persistent steatohepatitis. These findings suggested a connection between hepatic immune response and activation of HSPCs in MAFLD. Meanwhile, this investigation revealed the long-term immunological properties of the liver following temporary metabolic stress, which was independent of bone marrow haematopiesis and altered by age.