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Introduction: Since the first discovery of microRNAs (miRs) extensive evidence reveals their indispensable role in different patho-physiological processes. They are recognized as critical regulators of hepatic regeneration, as they modulate multiple complex signaling pathways affecting liver regeneration. MiR-related translational suppression and degradation of target mRNAs and proteins are not limited to one specific gene, but act on multiple targets., Areas Covered: In this review, we are going to explore the role of miRs in the context of liver regeneration and discuss the regulatory effects attributed to specific miRs. Moreover, specific pathways crucial for liver regeneration will be discussed, with a particular emphasis on the involvement of miRs within the respective signaling cascades., Expert Opinion: The considerable amount of studies exploring miR functions in a variety of diseases paved the way for the development of miR-directed therapeutics. Clinical implementation has already shown promising results, but additional research is warranted to assure safe and efficient delivery. Nevertheless, given the broad functional properties of miRs and their critical involvement during hepatic regeneration, they represent an attractive treatment target to promote liver recovery after hepatic resection.

Background & Aims: Surgical resection of the cancerous tissue represents one of the few curative treatment options for neoplastic liver disease. Such partial hepatectomy (PHx) induces hepatocyte hyperplasia, which restores liver function. PHx is associated with bacterial translocation, leading to an immediate immune response involving neutrophils and macrophages, which are indispensable for the priming phase of liver regeneration. Additionally, PHx induces longer-lasting intrahepatic apoptosis. Herein, we investigated the effect of apoptotic extracellular vesicles (aEVs) on neutrophil function and their role in this later phase of liver regeneration., Methods: A total of 124 patients undergoing PHx were included in this study. Blood levels of the apoptosis marker caspase-cleaved cytokeratin-18 (M30) and circulating aEVs were analyzed preoperatively and on the first and fifth postoperative days. Additionally, the in vitro effects of aEVs on the secretome, phenotype and functions of neutrophils were investigated., Results: Circulating aEVs increased at the first postoperative day and were associated with higher concentrations of M30, which was only observed in patients with complete liver recovery. Efferocytosis of aEVs by neutrophils induced an activated phenotype (CD11b high CD16 high CD66b high CD62L low ); however, classical inflammatory responses such as NETosis, respiratory burst, degranulation, or secretion of pro-inflammatory cytokines were not observed. Instead, efferocytosing neutrophils released various growth factors including fibroblast growth factor-2 and hepatocyte growth factor (HGF). Accordingly, we observed an increase of HGF-positive neutrophils after PHx and a correlation of plasma HGF with M30 levels., Conclusions: These data suggest that the clearance of PHx-induced aEVs leads to a population of non-inflammatory but regenerative neutrophils, which may support human liver regeneration., Lay Summary: In this study, we show that the surgical removal of a diseased part of the liver triggers a specific type of programmed cell death in the residual liver tissue. This results in the release of vesicles from dying cells into the blood, where they are cleared by circulating immune cells. These respond by secreting hepatocyte growth factors that could potentially support the regeneration of the liver remnant., Competing Interests: Conflict of interests Thomas Hammond is employed by and is a shareholder in AstraZeneca. All other authors declare no conflicts. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)