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Liver Regeneration



Upon the loss or damage of a portion of the total amount of liver parenchymal tissue, remaining hepatocytes recover from their cell cycle arrest and replenish thus the liver, to improve normal homeostasis. It has been shown that hepatocytes are capable of dividing at least 69 times during a life time [31]. To study this type of liver regeneration, most experimental models are based on surgically removing at least 70 % of the liver (partial hepatectomy, PH). This model results in hepatocyte proliferation without inflammatory events which makes it relatively easy to investigate this type of regeneration. The mechanisms involved in hepatocellular regeneration after PH are still poorly understood.

Theoretically, every hepatocyte is after 70% PH exposed to three-times the amount of factors received from the portal vein. However, the impact of this increased flow has not been fully investigated. Most studies are based on the initiation of liver regeneration without including the termination phase. It would also be interesting to understand which signals halt liver growth [32]. In a healthy liver, a unique pericentral hepatocyte population, characterised by the expression of Axis inhibition protein 2 (Axin2), slowly replenishes hepatocytes from the central vein towards the portal vein [33]. This process is sometimes also referred to as “the streaming liver” and is still under debate.

Streaming liver was originally hypothesised as proliferating and differentiating progenitor cells from the portal to the central vein over time [34]. In a study by Furuyama et al. in 2009 they followed biliary epithelial cells using SOX9 lineage tracing, supporting this hypothesis. They found proliferating SOX9-positive cells in the whole liver parenchyma, migrating from the periportal to the pericentral area during liver regeneration [35]. In contrast, subsequent studies could not confirm these findings [36, 37]. Recent research showed that these SOX9 positive cells are small hepatocytes close to the Canal of Hering [38]. There is to date still no consensus about the existence of  the streaming liver”.


Hepatocyte-mediated regeneration is not sufficient after massive loss of parenchymal cells or when hepatocytes become senescent (incapable to proliferate) after long-term liver damage. During persistent and severe liver damage, hepatocytes lose their regenerative capacity whereby epithelial cells become activated and begin to expand. This process is often referred to as an ductular reaction (DR), oval cell response or oval cell hyperplasia. These specialized epithelial cells are called adult stem cells or liver progenitor cells (LPCs) since they were shown to be able to differentiate into cholangiocytes andhepatocyte. Such LPCs exist in the Canals of Hering (CoH), located in the smallest and most peripheral braches of the biliary tree (Figure 1) [39, 40]. The CoH is also surrounded by other cells like HSCs, KCs, hepatocytes, LSECs and lymphocytes which all contribute to the DR. These niche cells produce and secrete ECM, like laminin [41], that retains many molecules secreted by the niche cells [41-44]. ECM is one of the most important drivers for LPC activation. Van Hul et al. showed that ECM deposition and activation of matrix-producing cells are essential to LPC activation and migration in a damaged mouse liver [44]. A key component of the ECM that drives LPC maintenance, expansion and migration is laminin. An in vitro study of LPC cultures showed that LPC expansion is only supported by the presence of laminin and not collagen [45]. The amount of ECM-producing cells, like myofibroblast, also increases along with the degree of the DR. Additionally, this DR in rodent models and in severe human liver diseases is always surrounded by laminin [41]. Galectin-3 (Gal-3, aka MAC-2), a laminin binding lectin, is a known macrophage marker in several tissues but is also expressed in ductal cells [46, 47]. Hsieh et al. showed that Gal-3-/- mice demonstrated reduction in macrophage infiltration and lacked DR in a steatotic LPC model whereas this resulted in a significant reduction in LPC expansion during cholangitis [47]. This shows how important laminin and its binding lectin is for LPC activation in injured livers.


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