Elucidating the role of macrophages in liver regeneration and tissue unit formation

ended

The liver, unlike many other tissues, has the ability to rapidly regenerate and restore function following tissue damage or surgical resection. This regenerative capacity has been recognized as far back as the ancient Greeks, who described it in the myth of Prometheus. Despite this, the precise molecular and cellular mechanisms underpinning the regeneration process are yet to be fully elucidated. Macrophages (Macs) have been proposed to play a role in regeneration but it has not been clear if these are Kupffer cells (KCs), the tissue resident macs of the liver, or macs recruited during the regeneration process (rMacs). Previously available tools have not allowed a distinction to be drawn between these cells. Within the liver KCs and/or rMacs are in close proximity to hepatocytes, hepatic stellate cells (HSC) and particularly liver sinusoidal endothelial cells (LSECs), these cells together with liver macrophages can be thought of as a tissue unit, which needs to be rebuilt as the liver regenerates. Adopting this tissue unit view of the liver, we hypothesize that these cells interact with one another forming a stable circuit, the maintenance of which is required for normal liver regeneration. Here we propose the use of novel and innovative tools including KC and tissue unit cell-specific knock in mice to study cell-cell cross-talk and conclusively determine the cell-circuit signals driving the formation of new functional units within the liver. With donor organs in short supply this project has the potential to uncover pro-regenerative therapies that are so desperately needed.