Macrophage WNT signalling in liver disease and regeneration
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Date
30/08/2022Item status
Restricted AccessEmbargo end date
30/08/2023Author
Horcas Lopez, Marta
Metadata
Abstract
Liver disease is still a clinical challenge.
Even though the liver has a
regenerative capacity, it can be impaired during acute or chronic injuries.
Paracetamol overdose is the leading cause of acute liver injury in the US and
UK. It can progress to liver failure in which liver transplantation is the sole
treatment. Chronic liver injury also represents a clinical burden that can
progress to cirrhosis and cancer. As there are no effective treatments to cure
these diseases, there is the need to seek alternative treatments. Macrophage
targeting is a promising approach to treat liver injured patients. WNT signalling
has been shown to play important roles in liver regeneration and cancer
progression. Since macrophages are a source of WNTs implicated in several
diseases, it was hypothesised that macrophage WNT signalling could be
modulated to stop disease progression or enhance liver regeneration. Two
different in vivo models were used to study the role of macrophage WNT
signalling in liver disease and regeneration. The first model was a Ctnnb1
deletion on Csf1r-expressing cells (referred to as β-catenin KO), in which
myeloid cells did not respond to WNTs.
The second model was a Porcupine
deletion on Csf1r-expressing cells (Porcn KO), in which myeloid cells did not
secrete WNTs. To determine the role of β-catenin signalling in macrophage
polarisation, β-catenin WT and KO bone marrow-derived macrophages were
polarised towards tissue repair-like or inflammatory-like phenotypes and
submitted for bulk RNA-Sequencing.
Deletion of β-catenin resulted in minimal
changes that suggested a mild macrophage phenotype. The macrophage
response to WNTs or their WNT secretion was not essential in a paracetamol
overdose model in mice. WT and KO mice regenerated similarly and did not
have any differences in macrophage infiltration into injured sites. In a model of
chronic liver injury by DDC diet, macrophage WNT signalling played a role in
disease progression. Even though macrophages did not respond to WNTs,
inhibition of macrophage WNT secretion resulted in increased fibrotic levels
on Porcn KO mice. Progression to this disease can cause
cholangiocarcinoma. Thus, using a cholangiocarcinoma model, Porcn KO
mice suggested to have a lower tumour load compared to their littermate
controls. However, macrophages were not responding to WNTs during cancer
progression. These studies showed that the liver repair mechanisms are injury
dependent and while macrophage WNT signalling is playing a role in some
conditions, further studies are needed to understand the pathways involved to
develop effective treatments.