LiverMacRegenCircuit · Elucidating the role of macrophages in liver regeneration and tissue unit formation
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-09-01 → 2022-08-31
- EU contribution
- €166,320
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Elucidating the role of macrophages in liver regeneration and tissue unit formation
The liver is a highly regenerative organ, able to efficiently restore mass and function following toxin, viral or surgically induced tissue damage, as long as the damage remains limited. However, with a growing incidence of persistent hepatitis infection, alcoholism and metabolic disorders, acute and chronic liver failure is becoming increasingly prevalent, associated with high morbidity and mortality. Currently, one of the main treatments for liver failure is transplantation, with more than 5,500 liver transplants occurring in Europe annually. However, the side effects of immunosuppression, cost and limited supplies of donor organs have prevented its broader application. As such, there is a desperate need for a greater understanding of the regeneration process and development of pro-regenerative therapies. This project studies the cellular and molecular mechanisms driving liver regeneration. We will use single-cell sequencing and spatial transcriptomics to track the cell-cell interactions during liver regeneration. By better understanding the molecular mechanisms at play, we hope to pave the way towards novel therapeutic interventions that could boost liver regeneration in patients and prevent the need for liver transplantation. The project has achieved most of its objectives and milestones for the period, with relatively minor deviations. We are finalizing the last part of WP4 for the moment. We are currently blocking one of the key cell-cell interactions we have identified to be increased specifically during liver regeneration. We believe this is part of a central liver regeneration program and are currently assessing the role of this program in liver regeneration. Our preliminary data are very promising and show an effect of regeneration but this needs to be repeated and further characterized. Once this is done we will be able to finalize our second publication for this project. We expect this to be ready within the next 6 months.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium
Links
Data: CORDIS, © European Union