title: Hedgehog pathway mediates early acceleration of liver regeneration induced by a novel two-staged hepatectomy in mice.
abstract: ALPPS, a novel two-staged approach for the surgical removal of large/multiple liver tumors, combines portal vein ligation (PVL) with parenchymal transection. This causes acceleration of compensatory liver growth, enabling faster and more extensive tumor removal. We sought to identify the plasma factors thought to mediate the regenerative acceleration following ALPPS.
  
  
  
  We compared a mouse model of ALPPS against PVL and additional control surgeries (n=6 per group). RNA deep sequencing was performed to identify candidate molecules unique to ALPPS liver (n=3 per group). Recombinant protein and a neutralizing antibody combined with appropriate surgeries were used to explore candidate functions in ALPPS (n=6 per group). Indian hedgehog (IHH/Ihh) levels were assessed in human ALPPS patient plasma (n=6).
  
  
  
  ALPPS in mouse confirmed significant acceleration of liver regeneration relative to PVL (p<0.001). Ihh mRNA, coding for a secreted ligand inducing hedgehog signaling, was uniquely upregulated in ALPPS liver (p<0.001). Ihh plasma levels rose 4h after surgery (p<0.01), along with hedgehog pathway activation and subsequent cyclin D1 induction in the liver. When combined with PVL, Ihh alone was sufficient to induce ALPPS-like acceleration of liver growth. Conversely, blocking Ihh markedly inhibited the accelerating effects of ALPPS. In the small cohort of ALPPS patients, IHH tended to be elevated early after surgery.
  
  
  
  Ihh and hedgehog pathway activation provide the first mechanistic insight into the acceleration of liver regeneration triggered by ALPPS surgery. The accelerating potency of recombinant Ihh, and its potential effect in human ALPPS may lead to a clinical role for this protein.
  
  
  
  ALPPS, a novel two-staged hepatectomy, accelerates liver regeneration, thereby helping to treat patients with otherwise unresectable liver tumors. The molecular mechanisms behind this accelerated regeneration are unknown. Here, we elucidate that Indian hedgehog, a secreted ligand important for fetal development, is a crucial mediator of the regenerative acceleration triggered by ALPPS surgery.
authors: Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland.
authors: Magda
authors: M
authors: Langiewicz
authors: Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland.
authors: Andrea
authors: A
authors: Schlegel
authors: Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland.
authors: Enrica
authors: E
authors: Saponara
authors: Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland.
authors: Michael
authors: M
authors: Linecker
authors: Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland.
authors: Pieter
authors: P
authors: Borger
authors: Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland.
authors: Rolf
authors: R
authors: Graf
authors: Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland.
authors: Bostjan
authors: B
authors: Humar
authors: Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland. Electronic address: clavien@access.uzh.ch.
authors: Pierre A
authors: PA
authors: Clavien
mesh_terms: D000818:Animals; D053823:Hedgehog Proteins / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006498:Hepatectomy / Q000379:methods*; D006801:Humans; D008026:Ligation; D008113:Liver Neoplasms / Q000097:blood / Q000098:blood supply / Q000601:surgery; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011169:Portal Vein / Q000601:surgery; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D053823:Hedgehog Proteins; C509246:IHH protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; C514061:ihh protein, mouse
keywords: Accelerator; Compensatory hypertrophy; Contralateral growth; Gene expression profiling; Hedgehog proteins; Hepatectomy; Liver regeneration; Morphogenic ligand