Exploration of the Transcriptional Landscape of ALPPS Reveals the Pathways of Accelerated Liver Regeneration

Abstract

Background and Aims: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), a novel 2-staged hepatectomy, dramatically accelerates liver regeneration and thus enables extensive liver tumor resection. The signaling networks underlying the ALPPS-induced accelerated regeneration process are largely unknown.Methods: We performed transcriptome profiling (TP) of liver tissue obtained from a mouse model of ALPPS, standard hepatectomy (68% model), and additional control surgeries (sham, PVL and Tx). We also performed TP using human liver biopsies (n = 5) taken from the occluded lobe and the future liver remnant (FLR) during the first step of ALPPS surgery (4–5 h apart). We used Oncofinder computational tools, which covers 378 ISPs, for unsupervised, unbiased quantification of ISP activity.Results: Gene expression cluster analysis revealed an ALPPS specific signature: the IGF1R Signaling Pathway (Cell survival), the ILK Pathway (Induced cell proliferation), and the IL-10 Pathway (Stability determination) were significantly enriched, whereas the activity of the Interferon Pathway (Transcription) was reduced (p < 0.05). Further, the PAK- and ILK-associated ISPs were activated at an earlier time point, reflecting significant acceleration of liver regeneration (p < 0.001). These pathways, which were also recovered in human liver biopsies, control cell growth and proliferation, inflammatory response, and hypoxia-related processes.Conclusions: ALPPS is not a straightforward addition of portal vein ligation (PVL) plus transection—it is more. The early stages of normal and accelerated liver regeneration are clearly discernible by a significantly increased and earlier activation of a small number of signaling pathways. Compounds mimicking these responses may help to improve the ALPPS method and further reduce the hospitalization time of the patient.

Conventional Two-Stage Hepatectomy or Associating Liver Partitioning and Portal Vein Ligation for Staged Hepatectomy for Colorectal Liver Metastases? A Systematic Review and Meta-Analysis

“…The underlying mechanisms responsible for this strong hypertrophic stimulus remain largely unclear, but some valuable insights could be gained from the circulatory cytokine profiles. Experimental assays have demonstrated that compared with those receiving liver transection alone or PVL, mice undergoing ALPPS showed significantly accelerated liver hypertrophy relative to those receiving either liver transection alone or PVL, indicating a potentially less pronounced role of microcirculation discontinuity ( 52 , 54 ). The gene expressions of promitogenic cytokines in regenerating the FLR and serum IL-6 levels were significantly increased in ALPPS-treated mice, with analogous results in human.…”

Hepatectomy-Induced Alterations in Hepatic Perfusion and Function - Toward Multi-Scale Computational Modeling for a Better Prediction of Post-hepatectomy Liver Function

“…Gene expression studies are useful to identify signaling pathways that are most affected by a given procedure. A number of studies have been performed focusing on PHx and confirmed the relevance of cell cycle associated genes in the process of liver regeneration (Borger et al, 2019;Colak et al, 2020).…”

“…The group with PVL had significantly higher survival compared with the control group, which was associated with greater upregulation of CCND1. Borger et al (2019) performed transcriptome profiling on two different mouse models to identify pathways associated with liver regeneration. One group underwent ALPPS, while the other group underwent PVL followed by transection.…”

Mitochondrial dysfunction attenuates rapid regeneration in livers with toxin-induced fibrosis

“…Although preliminary studies have shown that mitochondrial function, hypoxia signals, and the pathways above are involved in ALPPS-induced regeneration, there is a lack of robust evidence to support the causality (7)(8)(9)(10)15). A deeper understanding of the activation of HSCs and the JNK1/IHH axis has been demonstrated as the first example of an ALPPS-induced molecular event associated with unprecedented regenerative acceleration (7,16).…”

“…The Indian Hedgehog (IHH) pathway, mitochondrial function, and the transcriptional landscape during ALPPSinduced regeneration have been previously illustrated (7)(8)(9)(10). However, attenuation of regeneration in livers with fibrosis during ALPPS has not been well documented.…”