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2014 ; 63
(8
): 1333-44
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Myofibroblastic cells function as progenitors to regenerate murine livers after
partial hepatectomy
#MMPMID24173292
Swiderska-Syn M
; Syn WK
; Xie G
; Krüger L
; Machado MV
; Karaca G
; Michelotti GA
; Choi SS
; Premont RT
; Diehl AM
Gut
2014[Aug]; 63
(8
): 1333-44
PMID24173292
show ga
OBJECTIVE: Smoothened (SMO), a coreceptor of the Hedgehog (Hh) pathway, promotes
fibrogenic repair of chronic liver injury. We investigated the roles of SMO+
myofibroblast (MF) in liver regeneration by conditional deletion of SMO in ?
smooth muscle actin (?SMA)+ cells after partial hepatectomy (PH). DESIGN:
?SMA-Cre-ER(T2)×SMO/flox mice were treated with vehicle (VEH) or tamoxifen (TMX),
and sacrificed 24-96?h post-PH. Regenerating livers were analysed for
proliferation, progenitors and fibrosis by qRT-PCR and quantitative
immunohistochemistry (IHC). Results were normalised to liver segments resected at
PH. For lineage-tracing studies, ?SMA-Cre-ER(T2)×ROSA-Stop-flox-yellow
fluorescent protein (YFP) mice were treated with VEH or TMX; livers were stained
for YFP, and hepatocytes isolated 48 and 72?h post-PH were analysed for YFP by
flow cytometric analysis (FACS). RESULTS: Post-PH, VEH-?SMA-SMO mice increased
expression of Hh-genes, transiently accumulated MF, fibrosis and liver
progenitors, and ultimately exhibited proliferation of hepatocytes and
cholangiocytes. In contrast, TMX-?SMA-SMO mice showed loss of whole liver SMO
expression, repression of Hh-genes, enhanced accumulation of quiescent HSC but
reduced accumulation of MF, fibrosis and progenitors, as well as inhibition of
hepatocyte and cholangiocyte proliferation, and reduced recovery of liver weight.
In TMX-?SMA-YFP mice, many progenitors, cholangiocytes and up to 25% of
hepatocytes were YFP+ by 48-72?h after PH, indicating that liver epithelial cells
were derived from ?SMA-YFP+ cells. CONCLUSIONS: Hh signalling promotes transition
of quiescent hepatic stellate cells to fibrogenic MF, some of which become
progenitors that regenerate the liver epithelial compartment after PH. Hence,
scarring is a component of successful liver regeneration.
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