Liver tissue samples of mice that underwent ALPPS, Transection, PVL, Left Lateral resection, or Sham at varying time points.

Background & Aims: Occlusion of one liver section by portal vein ligation (PVL) induces compensatory liver regeneration in the remaining part. PVL-induced liver growth is being exploited for the surgical removal of large/multiple liver tumors. A novel approach coined ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatecomy) combines PVL with parenchymal transection and massively accelerates compensatory growth, enabling much faster and more extensive tumor removal. Regenerative acceleration following ALPPS seems to be mediated by plasma factors, which we sought to identify. Methods: We compared a mouse model of ALPPS against PVL and additional control surgeries. Gene expression profiling was performed to identify candidate molecules unique to ALPPS liver. Recombinant protein and neutralizing antibody combined with appropriate surgeries were used to explore candidate function in ALPPS. Results: ALPPS in mouse confirmed formidable acceleration of liver regeneration relative to PVL. Ihh, a secreted ligand inducing hedgehog signaling, was uniquely upregulated in ALPPS liver. Ihh plasma levels rose 4h after surgery, 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 human plasma, IHH was elevated early after ALPPS surgery. Conclusions: 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 elevations in human ALPPS suggest clinical potential for this morphogenic protein.