ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration.
OBJECTIVE
To develop a reproducible animal model mimicking a novel 2-staged hepatectomy (ALPPS: Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy) and explore the underlying mechanisms.


BACKGROUND
ALPPS combines portal vein ligation (PVL) with liver transection (step I), followed by resection of the deportalized liver (step II) within 2 weeks after the first surgery. This approach induces accelerated hypertrophy of the liver remnant to enable resection of massive tumor load. To explore the underlying mechanisms, we designed the first animal model of ALPPS in mice.


METHODS
The ALPPS group received 90% PVL combined with parenchyma transection. Controls underwent either transection or PVL alone. Regeneration was assessed by liver weight and proliferation-associated molecules. PVL-treated mice were subjected to splenic, renal, or pulmonary ablation instead of hepatic transection. Plasma from ALPPS-treated mice was injected into mice after PVL. Gene expression of auxiliary mitogens in mouse liver was compared to patients after ALPPS or PVL.


RESULTS
The hypertrophy of the remnant liver after ALPPS doubled relative to PVL, whereas mice with transection alone disclosed minimal signs of regeneration. Markers of hepatocyte proliferation were 10-fold higher after ALPPS, when compared with controls. Injury to other organs or ALPPS-plasma injection combined with PVL induced liver hypertrophy similar to ALPPS. Early initiators of regeneration were significantly upregulated in human and mice.


CONCLUSIONS
ALPPS in mice induces an unprecedented degree of liver regeneration, comparable with humans. Circulating factors in combination with PVL seem to mediate enhanced liver regeneration, associated with ALPPS.
*Laboratory of the Swiss HPB and Transplant Center, Department of Surgery, University Hospital Zurich, Zurich, Switzerland. †Hospital Paul Brousse, Université Paris Sud, Paris, France.
Andrea
A
Schlegel
Mickael
M
Lesurtel
Emmanuel
E
Melloul
Perparim
P
Limani
Christoph
C
Tschuor
Rolf
R
Graf
Bostjan
B
Humar
Pierre A
PA
Clavien
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002763:Cholecystectomy; D004797:Enzyme-Linked Immunosorbent Assay; D006498:Hepatectomy / Q000379:methods*; D006801:Humans; D006984:Hypertrophy; D007668:Kidney / Q000601:surgery; D008026:Ligation; D008115:Liver Regeneration; D008168:Lung / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011169:Portal Vein / Q000601:surgery; D060888:Real-Time Polymerase Chain Reaction; D013154:Spleen / Q000601:surgery
D015415:Biomarkers