Hepatic regeneration conteracts hepatic atrophy following portal vein ligation : intrahepatic size regulation in surgical models of simultaneous stimuli

The two-stage hepatectomy is performed if the future remnant liver is too small for the patient with large liver tumor. The two-stage procedure consists of portal vein occlusion as first step and partial resection (PHx) of the occluded lobe as second step, since portal vein occlusion induces hypertrophy of the future remnant liver. Frequently, atypical PHx of metastases is performed in addition to portal vein ligation (PVL). However, it is unclear how the additional PHx affects intrahepatic size regulation. Therefore, I investigated the underlying regulatory processes in case of concurrent stimuli to potentially modulate the size adaption process according to the need of the patient. firstly, I established a workflow to generate and analyze liver images. Then, I established an Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) model to explore the effect of inter-lobar collateral formation. To investigate the effect of a simultaneous PHx, I developed a novel surgical model of 20%PVL+70%PHx. At last, a model of 70%PVL+20%PHx was developed to investigate the effect of regeneration and atrophy stimulus on the deportalized liver. Prevention of collateral formation accelerated hypertrophy of the future remnant liver lobes and augmented atrophy of the deportalized liver lobes. PHx prevented atrophy of the deportalized liver lobe by inducing hepatocyte proliferation despite the lack of portal supply and, especially, by down-regulation of hepatic apoptosis. The formation of porto-portal collaterals played an important role in intrahepatic size regulation. We demonstrated for the first time that hepatocyte proliferation and apoptosis can be induced in the same liver lobe despite portal deprivation. This observation challenges the widespread assumption of the essential role of portal flow in liver regeneration.