Zhangyuting He , Hua-Yu Yang

a Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

b Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

The liver has roles in many processes, including metabolism,synthesis, and biotransformation.It is unique among all visceral organs, as it even can regenerate after injury.A common research model of liver regeneration is the 2/3 partial hepatectomy (PHx)model in animals, like rodents, in which the left lateral, left medial,and right medial hepatic lobes are surgically removed [1].Moreover, with the ability of hepatocyte hypertrophy and hyperplasia,within 7-10 days, the rest liver regenerates to its original size [2].Jo and colleagues [3]reported that splanchnic vasoactive agents could decrease portal vein pressure to facilitate the liver regeneration after 70% hepatectomy.However, liver regeneration and function maintenance need adequate mass of future remnant liver.Inadequate mass of future remnant liver results in liver failure which loses the opportunity for the liver to regenerate and therefore, it is important to keep an adequate future remnant liver to avoid posthepatectomy liver failure [4].

The mechanism of hepatocyte regeneration needs further studies.It is well accepted that hepatocyte regeneration is via two pathways; one is self-duplication, the other is dedifferentiation of mature hepatocytes into liver progenitor cells (LPCs), and the later further differentiate to hepatocytes and expand hepatocytes in large quantities [5].

The Hippo pathway and its downstream effectors, and the transcriptional co-activators Yes-associated protein (YAP), regulate organ growth and cell plasticity during body development and repairment [6].Sun et al.[7]confirmed that mechanical tensioninduced stress fiber formation and subsequent YAP activation are required to start the progress of hepatocyte dedifferentiation.With a small molecule cocktail targeting actin dynamics, hepatocytes could maintain their expression of functional genes likealbuminandHnf4α.One of the cocktails is XAV939, which can suppress YAP activity by stabilizing angiomotin family proteins through tankyrase inhibition.It means that YAP could be activated by physical resources, thus helping hepatocytes start dedifferentiation.So et al.[8]showed two major liver regeneration modes: the proliferation of preexisting hepatocytes and the LPCs-driven.YAP activation is essential for LPCs activation.Meanwhile, Notch and Wnt/β-catenin pathways also take effect in LPCs differentiation.Hepatocytes in different areas might receive different signals.Thus their fates changed variably.Shao et al.[9]examined the location of hepatic stem cells and the concentration of lipopolysaccharide(LPS) in different areas.The conclusion is that a high level of LPS in the portal vein is related to active stem cell location, and LPS facilitates the dedifferentiation of hepatocytes into LPCs.More information was provided that LPS-induced reprogramming is linked with YAP activation because YAP expression is highly enriched after the administration of LPS.Tong et al.[10]explored the origin of newborn hepatocytes by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).Compared with LPCs driven by high expression of YAP, newborn hepatocytes of ALPPS are immature.It is more likely that ALPPS redistribution of portal blood flow triggers LPCs to restore normal liver structure and function.Through blood flow, the distribution of some chemical agents may regulate hepatocytes for different fates.Thus, we can guess that some hepatocytes could dedifferentiate to LPCs after the suitable activation of YAP.Wang et al.[11]found that aflatoxin B1 helps the proliferation, invasion, and dedifferentiation of LPCs by activating YAP pathways.Furthermore, postoperative liver regeneration may also contribute to tumor recurrence, which might result from abnormal YAP activation.After hepatectomy, inadequate future remnant liver can cause post-hepatectomy liver failure, meaning that the remnant cannot hold the capability for regeneration and body fundamental synthesis [4].Bou Saleh et al.[12]evaluated the YAP pathway in the background of alcoholic hepatitis.They also found that YAP in hepatocytes of alcoholic hepatitis is activated abnormally, which could lead to a loss of hepatocytes identity and impaired regeneration.Liver transplantation is always used to treat alcoholic hepatitis.However, relapse rates remain high.YAP activation is essential in the regeneration process, as it helps hepatocytes dedifferentiate to LPCs.More pathways are needed in LPCs-driven liver regeneration to control the cell fate, not towards carcinoma or abnormal proliferation.

Wnt/β-catenin signaling also contributes to liver regeneration.After a liver injury, such as PHx or toxicant-induced liver injury, activation of Wnt/β-catenin not only helps sustain the life-sustaining functions of the liver, such as synthesis, metabolism, and detoxification, but also replicates and regains the lost tissue [13].OlivaVilarnau et al.[1]established a 3D spheroid model of primary human hepatocytes to study this process.Primary human hepatocytes isolated from the native liver do acquire a regenerative phenotype as seeninvivoafter PHx, but this proliferation is limited.It is predicted that activation of Wnt/β-catenin and inhibition of p53 signaling are crucial for further regeneration.In their experiment, cell spheroids treated with Chir99021 (Wnt/β-catenin signaling activator) were significantly larger than those in the control group.Wnttarget genesAXIN2andLGR5also show a significantly increase.However, genes related to the metabolism of hepatocytes were not tested with Chir99021.Thus, the Wnt pathway activator does help hepatocytes, but the influence on differentiation and dedifferentiation is still not clear.Whether Wnt activation can be triggered through other mechanisms like Yap and Notch needs further exploration.

Notch signaling is essential for bile duct formation from liver regeneration.Minnis-Lyons et al.[14]found that Notch inhibition reduced biliary epithelial cells proliferation, which as a result, limited the dedifferentiation from biliary epithelial cells to hepatocytes.This signal is not a strict hepatocyte fate-promoting signal.Probably, we can guess it helps expand progenitor cells, like biliary epithelial cells or LPCs, before their differentiation.

In summary, studies on this topic always focus on animal models.Some studies attempt to adopt 3D-printing or 3D-culture skills,which can simulate cell microenvironmentinvivobetter than 2D.One can guess that after a severe liver injury, including surgery or drug toxicity, the residual liver would regenerate and compensate liver function.The hepatocyte regeneration is initiated by signals from other cells, and YAP pathway plays an important role.After the activation of LPCs, the Wnt pathway and Notch pathway help further proliferate and differentiate.More studies are needed in this field.

Acknowledgments

None.

CRediT authorship contribution statement

Zhangyuting He:Data curation, Investigation, Writing - original draft.Hua-Yu Yang:Conceptualization, Supervision, Writing -review & editing.

Funding

None.

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.