Molecular pathways of liver regeneration: A comprehensive review

Abstract

The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70% of its volume. Although knowledge of this phenomenon dates back to Greek mythology (the story of Prometheus), many aspects of liver regeneration are still not understood. A variety of different factors, including inflammatory cytokines, growth factors, and bile acids, promote liver regeneration and control the final size of the organ during typical regeneration, which is performed by mature hepatocytes, and during alternative regeneration, which is performed by recently identified resident stem cells called “hepatic progenitor cells”. Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass, such as in cases of chronic injury or excessive acute injury. In liver maintenance, the body mass ratio is essential for homeostasis because the liver has numerous functions; therefore, a greater understanding of this process will lead to better control of liver injuries, improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases. The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries. Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.

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

“…They respond with an increase in vasoactive compounds like NO (Bartels and Hildebrand, 1975 ; Poisson et al, 2017 ), mediated by KLF2-dependent induction of, besides others, NO synthase (Parmar et al, 2006 ). NO regulates the regenerative response after PHx by orchestrating a cytokine network that includes HGF and IL6 to prime hepatocytes for proliferation and TGFβ as the growth terminating signal (Yagi et al, 2020 ; de Rudder et al, 2021 ; Kiseleva et al, 2021 ). Regulation of liver regeneration after partial hepatectomy by LSEC-mediated mechanical forces was predicted using a computational 3D network of sinusoids substantiating the functional link between hepatic flow control and liver regeneration (Ishikawa et al, 2021 ).…”

Orosomucoid in liver diseases

“…Therefore, eliminating arrest-promoting mechanisms affects the growth of differentiated hepatocytes; in other words, proliferation plays a key role in overcoming liver failure. Although some mitogens, such as growth factors, have been shown to affect proliferation, in recent years, paracrine mediators and nonmitogenic cytokines, including ORM1, have also been shown to participate in the control of this process in a coordinated manner[ 14 ]. Indeed, ORM1 expression increases during regeneration following liver resection in both humans and mice[ 15 ].…”

Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection

“…In tumorigenesis, the different pathways activated by HGF are ERK1/2/MAPK and PI3K/Akt [ 42 ], leading to the oxidation of heat shock protein 60 and protein disulfide isomerase-induced ERK, and the migration of tumor cells [ 36 , 43 ]. On the other hand, these signaling cascades are known to be the classical pro-survival pathways involved in the reduction of liver injury, and improved liver regeneration after hepatic resections and LT [ 44 ]. As in the HGF-cMet axis, the activation of such pro-survival pathways protect against liver injury and promote liver regeneration, but their failure might promote tumor development in the presence of undetectable micrometastases.…”