Principles of Liver Regeneration and Growth Homeostasis

Abstract

Liver regeneration is perhaps the most studied example of compensatory growth aimed to replace loss of tissue in an organ. Hepatocytes, the main functional cells of the liver, manage to proliferate to restore mass and to simultaneously deliver all functions hepatic functions necessary to maintain body homeostasis. They are the first cells to respond to regenerative stimuli triggered by mitogenic growth factor receptors MET (the hepatocyte growth factor receptor] and epidermal growth factor receptor and complemented by auxiliary mitogenic signals induced by other cytokines. Termination of liver regeneration is a complex process affected by integrin mediated signaling and it restores the organ to its original mass as determined by the needs of the body (hepatostat function). When hepatocytes cannot proliferate, progenitor cells derived from the biliary epithelium transdifferentiate to restore the hepatocyte compartment. In a reverse situation, hepatocytes can also transdifferentiate to restore the biliary compartment. Several hormones and xenobiotics alter the hepatostat directly and induce an increase in liver to body weight ratio (augmentative hepatomegaly). The complex challenges of the liver toward body homeostasis are thus always preserved by complex but unfailing responses involving orchestrated signaling and affecting growth and differentiation of all hepatic cell types.

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

“…This suggests the existence of the so-called hepatostat in liver biology that will regulate its size on the basis of the need for optimum function. 2,20 Although pathways such as transforming growth factor-b have been proposed to be mito-inhibitory for hepatocytes in culture, loss of its signaling did not have any impact on LR. 7,21 Recently, an important role of extracellular matrix in counterbalancing hepatic growth and eventually contributing to halt the LR process has been reported.…”

“…2 Although it is known for a long time that after surgical loss of hepatic mass, the remaining liver will regenerate to restore the previous mass and LR process will conclude as soon as the prehepatectomy mass is restored. This suggests the existence of the so-called hepatostat in liver biology that will regulate its size on the basis of the need for optimum function.…”

“…1 Liver is a unique organ in its ability to respond physiologically through nonestem celledependent regeneration after surgical or toxin-induced loss of hepatic mass. 2 After partial hepatectomy (PH), several signaling pathways get activated in tandem to ensure proper initiation and progression of the regenerative process, which entails orderly proliferation of all resident cells of the liver. 2 One pathway that is activated early during LR is the Wnt/b-catenin signaling pathway.…”

“…2 After partial hepatectomy (PH), several signaling pathways get activated in tandem to ensure proper initiation and progression of the regenerative process, which entails orderly proliferation of all resident cells of the liver. 2 One pathway that is activated early during LR is the Wnt/b-catenin signaling pathway. This pathway has been shown to be highly relevant in ensuring proper G 1 to S phase transition of hepatocytes through regulation of its key target, cyclin-D1.…”

Small‐for‐size grafts increase recurrence of hepatocellular carcinoma in liver transplantation beyond milan criteria

“…Liver regeneration triggered by shear stress caused by excessive portal blood flow is regulated by highly complex network signals, such as growth factors, cytokines, nuclear receptors, and hormones. (24) Liver regeneration stimulation signals increase as the size of the liver graft or remnant liver decreases. For instance, a significant increase in levels of adhesion kinase, vascular endothelial growth factor (VEGF), and early growth response 1 associated with cell adhesion, angiogenesis, and liver parenchymal and microvascular damage was observed in SFSG, (25,26) and this can provide a favorable microenvironment for the proliferation of tumor cells as well as normal hepatocytes.…”