studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 545A
678
Notch and Wnt control ductular reactions via the Igf1
axis
Sarah E. Minnis-Lyons 1 , Luke G. Boulter 2 , Tak Yung Man 1 , Michael
J. Williams 1 , Rachel V. Guest 1 , Wei-Yu Lu 1 , Noemi Van Hul 4 , Isabelle
A. Leclercq 4 , Owen J. Sansom 3 , Stuart J. Forbes 1 ; 1 MRC Centre
for Regenerative Medicine, Edinburgh, United Kingdom; 2 MRC
Human Genetics Unit, Edinburgh, United Kingdom; 3 Beatson Institute
for Cancer Research, Glasgow, United Kingdom; 4 Universite
Catholique de Louvain, Brussels, Belgium
Ductular reactions (DR) are seen in chronic liver injury when
hepatocyte regeneration is impaired and are thought to contain
putative hepatic progenitor cells (HPCs). Their ability to contribute
to large-scale parenchymal repair has been questioned.
Notch and Wnt are key signals required for liver development
and regeneration. Given their many actions include promoting
cell expansion, we sought to identify if these signals control
DRs after hepatocyte injury and importantly whether these
pathways can be manipulated for future therapeutic targeting.
Notch and Wnt pathways were analysed using a genetic in
vivo model of hepatocellular injury and ductular activation that
has allowed us to examine the temporal dynamics of the ductular
response (AhCre MDM2fl/fl). We have also used K19
and OPNCre lineage tracing tools, as well as HPC lines, to test
small molecules, blocking antibodies and genetic loss of function
in order to establish functionality and interactions of these
signalling pathways. We have found distinct time-dependent
Notch and Wnt signatures following hepatocyte injury. Small
molecule inhibitors have revealed time-sensitive windows; with
the early ductular proliferative response principally driven by
Notch and the later response driven by Wnt. Anti-Notch1
and Notch2 blocking antibodies and genetic loss of Notch3
have confirmed DRs are driven by Notch1 and Notch3 but
not Notch2. We have identified DRs as an additional source
of the potent growth hormone Igf1 and this production is Wnt
driven. Notch driven expression of Igf1-receptor within DRs
highlights this axis as a node for cooperation between Notch
and Wnt signals. Small molecule (AG1024) and genetic loss
of function (Igf1 receptor fl/fl) confirms functionality of this axis
and stresses a pivotal role for Igf1-receptor in the generation of
the ductular reaction which can be enhanced by administration
of recombinant Igf-1 (all P values =