Profiling Gene Programs in the Blood During Liver Regeneration in Living Liver Donors

Abstract

The human liver’s capacity to rapidly regenerate to a full‐sized functional organ after resection has allowed successful outcomes for living donor liver transplantation (LDLT) procedures. However, the ability to detect and track physiological changes occurring during liver regeneration after resection and throughout the restoration process is still lacking. We performed a comprehensive whole‐transcriptome RNA sequencing analysis of liver and circulating blood tissue from 12 healthy LDLT donors to define biomarker signatures for monitoring physiological activities during liver regeneration at 14 time points for up to a 1‐year procedural follow‐up. LDLT donor liver tissue differentially expressed 1238 coding and noncoding genes after resection, and an additional 1260 genes were selectively regulated after LDLT. A total of 15,011 RNA transcript species were identified in the blood in response to liver resection. The transcripts most highly regulated were sequentially expressed within 3 distinct peaks that correlated with sets of functional genes involved in the induction of liver resection–specific innate immune response (peak 1), activation of the complement system (peak 2), and platelet activation and erythropoiesis (peak 3). Each peak corresponded with progressive phases of extracellular matrix degradation, remodeling, and organization during liver restoration. These processes could be tracked by distinct molecular signatures of up‐regulated and down‐regulated gene profiles in the blood during phases of liver repair and regeneration. In conclusion, the results establish temporal and dynamic transcriptional patterns of gene expression following surgical liver resection that can be detected in the blood and potentially used as biomarker signatures for monitoring phases of liver regeneration.

Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration

“…We have shown that pharmacological activation of Nrf2 in primary human hepatocytes results in the modulation of genes that are associated with enhanced liver regeneration in Accepted Article mice treated with CDDO-Me. In addition, it has recently been reported that many of these processes are also modulated in the remnant liver within four hours of surgery in patients (34,35). These findings highlight the potential translational importance of our work.…”

The hippo pathway: A master regulator of liver metabolism, regeneration, and disease

“…The network analysis approach used on liver regeneration showed complex interactions between the Hippo signaling pathways with others signaling pathways including TNF-a, IL-6, IFN-γ (interferon-gamma), Hedgehog, Notch, TGF-β, and WNT. [192][193][194][195] TNF-α, IL-6, and IFN-γ signaling pathways display crucial roles in the induction of innate immune responses during the acute peak of liver regeneration, happening between 2 and 120 minutes after PHx, in donors and recipients of liver transplant. During this phase, different components of the innate immune system are recruited and activated into the injured liver, including macrophages, neutrophils, and mast cells, promoting activation of liver regeneration through IL-6 cytokine production.…”

“…During this phase, different components of the innate immune system are recruited and activated into the injured liver, including macrophages, neutrophils, and mast cells, promoting activation of liver regeneration through IL-6 cytokine production. 194 Inactivation of the Hippo signaling leads to recruitment of YAP/TAZ into the nucleus and form a complex with SMADS and β-Catenin, respectively, key components of the TGF-β and WNT signaling pathways, promoting the transcription of target genes that govern overall cell proliferation and tissue growth. 192 Upon liver injury, HSCs are activated and upregulate the expression of Jag1, the Notch ligand, through YAP, promoting Notch signaling and biliary specification in oval cells/hepatic pluripotent cells.…”

“…The network analysis approach used on liver regeneration showed complex interactions between the Hippo signaling pathways with others signaling pathways including TNF‐a, IL‐6, IFN‐γ (interferon‐gamma), Hedgehog, Notch, TGF‐β, and WNT 192‐195 . TNF‐α, IL‐6, and IFN‐γ signaling pathways display crucial roles in the induction of innate immune responses during the acute peak of liver regeneration, happening between 2 and 120 minutes after PHx, in donors and recipients of liver transplant.…”

Transcriptomic profiles of human livers undergoing rewarming machine perfusion before transplantation—first insights

“…The evolving technique of next-generation sequencing opened new doors for a deeper understanding of pathophysiological processes of liver regeneration, diseases and in the field of liver transplantation (Nicastro and D'Antiga 2018;Chen et al 2018;Lawrence et al 2019;Yang et al 2020). Indeed, the field of machine perfusion of liver allografts lacks the application of these new up-to-date techniques, which will yield to gain insights into the molecular principles that underlie the protective effects of allograft machine perfusion before liver transplantation.…”