Abstract
Recently, we have shown that an enhanced blood flow through the liver triggers hepatocyte proliferation and thereby liver growth. In this review, we first explain the literature on hepatic blood flow and its changes after partial hepatectomy (PHx), before we present the different steps of liver regeneration that take place right after the initial hemodynamic changes induced by PHx. Those parts of the molecular mechanisms governing liver regeneration, which are directly associated with the hepatic vascular system, are subsequently reviewed. These include β1 integrin-dependent mechanotransduction in liver sinusoidal endothelial cells (LSECs), triggering mechanically-induced activation of the vascular endothelial growth factor receptor-3 (VEGFR3) and matrix metalloproteinase-9 (MMP9) as well as release of growth-promoting angiocrine signals. Finally, we speculate how advanced age and obesity negatively affect the hepatic vasculature and thus liver regeneration and health, and we conclude our review with some recent technical progress in the clinic that employs liver perfusion. In sum, the mechano-elastic properties and alterations of the hepatic vasculature are key to better understand and influence liver health, regeneration, and disease.
Highlights
Recently, we have shown that an enhanced blood flow through the liver triggers hepatocyte proliferation and thereby liver growth
We first explain the literature on hepatic blood flow and its changes after partial hepatectomy (PHx), before we present the different steps of liver regeneration that take place right after the initial hemodynamic changes induced by PHx
Before molecules from the blood can reach the hepatocytes after crossing the liver sinusoidal endothelial cells (LSECs) layer, they must pass an extracellular space, called the space of Disse
Summary
That separate the blood from the hepatocytes (Figure 1C). ECs are adapted to the surrounding tissue (Aird 2007a, b). The LSECs in the hepatic sinusoids are fenestrated, lack a distinct basement membrane, and have unique junctional complexes (Braet and Wisse 2002; Géraud et al 2012; Sørensen et al 2015). These features likely allow LSECs to act as a selective sieve to facilitate (and, to some extent, regulate) the exchange of substances between blood and liver parenchyma. Hepatic stellate cells (HSCs), which are the pericytes of hepatic capillaries, are located within the space of Disse and maintain extracellular matrix (ECM) homeostasis in the normal liver (Häussinger and Kordes 2019). During development or acute injury, HSCs are activated to support hematopoiesis and regeneration (Sawitza et al 2009), while in chronic inflammation of the liver, HSCs contribute to progression of liver fibrosis by excessive production of ECM proteins (Friedman 2008)
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