Axon guidance molecules in liver pathology: Journeys on a damaged passport

Background and aims: The liver is an innervated organ that develops a variety of chronic liver disease (CLD). Axon guidance cues (AGCs), of which ephrins, netrins, semaphorins and slits are the main representative, are secreted or membrane-bound proteins that can attract or repel axons through interactions with their growth cones that contain receptors recognizing these messengers. While fundamentally implicated in the physiological development of the nervous system, the expression of AGCs can also be reinduced under acute or chronic conditions, such as CLD, that necessitate redeployment of neural networks.

Methods: This review considers the ad hoc literature through the neglected canonical neural function of these proteins that is also applicable to the diseased liver (and not solely their observed parenchymal impact).

Results: AGCs impact fibrosis regulation, immune functions, viral/host interactions, angiogenesis, and cell growth, both at the CLD and HCC levels. Special attention has been paid to distinguishing correlative and causal data in such datasets in order to streamline data interpretation. While hepatic mechanistic insights are to date limited, bioinformatic evidence for the identification of AGCs mRNAs positive cells, protein expression, quantitative regulation, and prognostic data have been provided. Liver-pertinent clinical studies based on the US Clinical Trials database are listed. Future research directions derived from AGC targeting are proposed.

Conclusion: This review highlights frequent implication of AGCs in CLD, linking traits of liver disorders and the local autonomic nervous system. Such data should contribute to diversifying current parameters of patient stratification and our understanding of CLD.