How Does a Single Cell Know When the Liver Has Reached Its Correct Size?

Abstract

The liver is a multi-functional organ that regulates major physiological processes and that possesses a remarkable regeneration capacity. After loss of functional liver mass the liver grows back to its original, individual size through hepatocyte proliferation and apoptosis. How does a single hepatocyte ‘know’ when the organ has grown to its final size? This work considers the initial growth phase of liver regeneration after partial hepatectomy in which the mass is restored. There are strong and valid arguments that the trigger of proliferation after partial hepatectomy is mediated through the portal blood flow. It remains unclear, if either or both the concentration of metabolites in the blood or the shear stress are crucial to hepatocyte proliferation and liver size control. A cell-based mathematical model is developed that helps discriminate the effects of these two potential triggers. Analysis of the mathematical model shows that a metabolic load and a hemodynamical hypothesis imply different feedback mechanisms at the cellular scale. The predictions of the developed mathematical model are compared to experimental data in rats. The assumption that hepatocytes are able to buffer the metabolic load leads to a robustness against short-term fluctuations of the trigger which can not be achieved with a purely hemodynamical trigger.

Intrahepatic Size Regulation in a Surgical Model: Liver Resection-Induced Liver Regeneration Counteracts the Local Atrophy following Simultaneous Portal Vein Ligation

“…Currently, two hypotheses regarding the initiation of liver atrophy and regeneration are discussed: (1) decreased intrahepatic shear stress leads to apoptosis [15], whereas elevated shear stress due to portal hypertension triggers hepatocyte proliferation [16,17,18,19,20], and (2) a decreased metabolic demand imposed on the individual liver lobe leads to atrophy, whereas an increased metabolic load imposed on the residual liver triggers hepatocyte proliferation after PHx or PVL [5,6]. …”

“…All slides were digitalized using a slide scanner (Nanozoomer; Hamamatsu Electronic Press Co., Ltd., Iwata, Japan). Morphological analysis focussed on the detection of single-cell necrosis, confluent necrosis, and sinusoidal dilatation as often-reported effects of PVL, as well as on the detection of signs indicative of hepatic outflow obstruction [5,6]. …”

“…Thus, hemodynamic and metabolic load hypotheses were proposed to explain the process of liver regeneration and liver size regulation. The hemodynamic hypothesis refers to the shear stress (portal hyperperfusion) in the hepatic sinusoids, while the metabolic load hypothesis refers to the metabolic demands (concentration of metabolites) imposed on the liver [5,6]. …”

Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer

“…Alternatively, partial hepatectomy increases blood flow to the remaining lobes, effectively upregulating the concentration of metabolic products and signaling molecules that may activate hepatocyte proliferation [52]. G protein coupled receptors (GPCRs) are an important link into the Hippo pathway that may sense increases in metabolites associated with hepatectomy.…”

Rodent Models and Imaging Techniques to Study Liver Regeneration

“…An integrated model allowing the prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration after CCl 4 intoxication is already available [93]. This model is currently being extended to incorporate the regenerative process after liver resection [94,95]. The final aim is a model that is composed of a larger battery of interconnected submodels representing liver anatomy and physiology, integrating processes across hierarchical levels in space, time and structural organization.…”