Human liver regeneration

The liver is a unique organ with an abundant regenerative capacity. Human liver is the only solid organ that uses regenerative mechanisms to ensure that the liver-to-bodyweight ratio is always at 100% of what is required for body homeostasis ¹. Other solid organs such as your lungs, kidneys and pancreas adjust to tissue loss but do not return to 100% of normal. Even when almost two-thirds of the liver is surgically removed, the remaining liver can rapidly restore its original size. In rodents, the remaining liver after 70% hepatectomy or 30% partial liver graft returns to a size of 100% in 7–10 days after the operation, with a peak in DNA synthesis in the first 3 days. In humans, restoration of the liver mass is complete around 3 months following right or left hepatectomy, with a peak in DNA synthesis at days 7–10 after the operation ². In living donor liver transplantation, Haga et al. ³ reported that the remaining left lobe of donors and left lobe graft of recipients regenerate more rapidly than the remaining right lobe of donors and right lobe graft of recipients. Moreover, liver regeneration rate is higher in the recipient’s left lobe graft than in the donor’s remaining left lobe ³. They also showed that the recipient liver volume increased rapidly in the first 2 months, exceeding the standard liver volume, and then gradually decreased to 90% of the standard liver volume ³. Mature hepatocytes (liver cells) are the source of new liver cells, not stem cells; however, stem cells play an important role in some cases of liver regeneration ⁴. Using genetic fate mapping and a high-throughput imaging system of individual hepatocytes, Miyaoka et al. ⁵ reported that the volume of hepatectomy affected the mode of liver regeneration; i.e., while the remnant liver following 30% partial hepatectomy regenerated solely by hypertrophy without cell division, hypertrophy and subsequent proliferation almost equally contributed to regeneration after 70% partial hepatectomy. Moreover, although most hepatocytes entered the cell cycle after 70% partial hepatectomy, only about half of the hepatocytes underwent cell division during liver regeneration, leading to an increase in hepatocyte ploidy ⁵. These results suggest that liver regeneration is a flexible and variable process that depends on the condition of the remaining liver, graft, and metabolic environment of the host. Partial hepatectomy also known as Minimally Invasive Liver Surgery, is surgery to remove a portion of the liver. Only people with good liver function who are healthy enough for surgery and who have a single liver tumor that has not grown into blood vessels can have this operation. Table 1 summarizes the main molecular factors in liver regeneration.

Human liver regenerative capacity is significantly impaired during chronic liver diseases due to the accumulation of senescent hepatocytes ⁶. In this case, liver mass restoration is performed by hepatic progenitor cells ⁷. Hepatic progenitor cells are located in the canals of Hering and have a bipotential nature; in other words, they can differentiate into both hepatocytes and biliary epithelial cells, the choice of which is determined by the activation of certain genes ⁸. The canals of Hering connect the hepatocyte canalicular system and the biliary tree, and such a location of hepatic progenitor cells is consistent with their bipotential features ⁹. Transplantation of current cells leads to liver regeneration enhancement via hepatic progenitor cell proliferation and differentiation, which can be applicable for the treatment of certain liver diseases ¹⁰. CK19, EpCAM and CD133 are markers common to both hepatic progenitor cells and biliary epithelial cells. Trop2 (Tacstd2) is a transmembrane molecule that is present on the hepatic progenitor cell surface and absent on biliary epithelial cells; therefore, it can play a role as a specific marker, similar to Foxl1 ¹¹.

The origin of hepatic progenitor cells is still being researched. Many scientists think that hepatic progenitor cells arise from mature differentiated biliary epithelial cells due to the presence of similar markers and cell localization. The expression of hepatocyte markers, such as albumin, AFP and HNF4α, appears earlier than hepatic progenitor cell expansion. Newly formed hepatic progenitor cells have various markers on their surface, including the biliary epithelial cell markers HNF1b and CK19, which are maintained until the hepatic progenitor cells differentiate into mature hepatocytes ¹². Hepatocytes and biliary epithelial cells are formed from common cells, called hepatoblasts, during the second trimester of embryonic development. Consequently, the possibility of hepatocyte to biliary epithelial cell transdifferentiation and vice versa is genetically feasible and might be programmed to form a facultative pool of progenitors ¹³.

Hepatic progenitor cell compartment activation in the human liver is called ductular reaction because of the role of ductular epithelium activation. In the niche, hepatic progenitor cells are surrounded by epithelial and nonparenchymal cells, immune cells, and the components of the ECM, which transport activating signals ¹⁴. As long as hepatic progenitor cells drive the regeneration of massive or chronic damage facilitated by immune cells, inflammatory cytokines, such as TNF-α, lymphotoxin-β, interferon-γ and IL-6, will play a crucial role in hepatic progenitor cell activation. TNF-like weak inducer of apoptosis (TWEAK) is a TNF superfamily member and the main inducer of hepatic progenitor cell activation ¹⁵. Macrophages and NK cells are primary sources of TWEAK ligands. The interaction with target cells is realized by FGF-inducible 14 receptors. The TWEAK/ FGF-inducible 14 interaction leads to ductular reaction initiation via activation of the NF-κB signaling pathway ¹⁶. Hepatic progenitor cell regulation is also performed by free oxygen radicals, which act as second messengers, realizing the balance between self-renewal and the differentiation of current cells. Low reactive oxygen species levels promote hepatic progenitor cell proliferation via extracellular-signal-regulated kinase 1/2, Jun 1/2, Wnt and NF-κB signaling ¹⁷.

Hepatic progenitor cell differentiation into hepatocytes and biliary epithelial cells is regulated by a variety of signaling pathways. FGF9, the HGF-с-MET signaling pathway ¹⁸ and oncostatin M activate AKT and STAT3, which are required for hepatic progenitor cell differentiation into hepatocytes, whereas HNF-6, HNF-1β and NOTCH signaling lead to biliary epithelial cell development ¹⁹. All-trans retinoic acid is a significant active metabolite of vitamin A that is involved in hepatic progenitor cell differentiation by increasing miR-200a expression, which regulates cell autophagy ²⁰. Ma et al ²¹ demonstrated the regulatory function of autophagy in hepatic progenitor cell differentiation into hepatocytes via activation of the Wnt/β-catenin signaling pathway. Autophagy can also regulate hepatic progenitor cell differentiation into biliary epithelial cells since it inhibits the Notch1 signaling pathway, which is required for the development of biliary duct cells. Therefore, autophagy is decreased during the early stages of liver regeneration ²².

Recently, a new pool of multipotential biliary progenitor cells, which can differentiate into hepatocytes, biliary epithelial cells and the islets of Langerhans cells, was identified in peribiliary glands, which are epithelial invaginations of extrahepatic and large intrahepatic biliary ducts ⁸. This pool was named biliary tree stem/progenitor cells (BTSCs). Biliary tree stem/progenitor cells express stem cell markers such as Sox17, Pdx1, Sox9, EpCAM, Sall4 and Lgr5 on their surface. Biliary tree stem/progenitor cells are primarily involved in biliary epithelium regeneration in chronic diseases such as primary sclerosing cholangitis, cholangiocarcinoma, nonanastomotic strictures and biliary atresia ²³.

Table 1. Main factors driving liver regeneration

Factor of regeneration	Influence on liver regeneration
TNF-α	Induction of CDK-1
IL-6	Activation of the JAK/STAT, MAPK, and PI3K/AKT signaling pathways
Hh signaling pathway	ECM remodulation; induction of progenitor cell and liver epithelial cell expansion; induction of glutaminolysis; inhibition of hepatocyte, biliary epithelial cell, Ito cell and progenitor cell apoptosis
ALR	lfALR: Enhancement of the hepatocyte response to IL-6 and STAT3 phosphorylation induction. MAPK signaling pathway activation; NK cells inhibition; increase in IL-6, TNFα and iNOS production by Kupffer cells, sfALR: Inhibition of proapoptotic stimuli
NRF2	Regulation of M phase entry, hepatocyte proliferation, maintenance of newly formed hepatocytes in a differentiated state
Growth factors (HGF, TGF-α, EGF, HB-EGF)	Stimulation of DNA synthesis and cell proliferation via Ras-MAPK and PI3K/AKT signaling pathway activation
Bile acids	Activation of CDK2, cell cycle, regulation of termination phase and terminate liver size, decrease in the inflammatory cytokine production, enhancement of bile acid excretion and HCO3ˉ, Clˉ secretion, control of BA polarity
Wnt-β-catenin	Hepatocyte proliferation induction
Notch signaling pathway	Modulation of hepatic progenitor cells differentiation toward biliary epithelial cells, regulation of hepatocyte proliferation, mitotic rhythms, cyclin E1, A2 and B1
IL-1	DNA synthesis inhibitor
SOCSs	c-MET and JAK-STAT signaling pathway inhibition
TGF-β1, activin A, BMPs	Induction of apoptosis to correct excessive liver mass
HNF4	Regulation of hepatocyte differentiation, initiation of the termination phase, antagonism YAP and TGF-β/SMAD3, prevention of excessive connective tissue synthesis, inhibition of hepatic progenitor cells proliferation and migration
Hippo/YAP signaling pathway	Terminal liver size control

Abbreviations: TNF-α = Tumor necrosis factor-α; IL-6 = Interleukin-6; CDK-1 = Cyclin-dependent kinase 1; JAK/STAT = Janus kinase/signal transducer and activator of transcription; Hh = Hedgehog; ECM = Extracellular matrix; MAPK = Mitogen-activated protein kinase; ALR = Augmenter of liver regeneration; lfALR = Long-form ALR; sfALR = Short-form ALR; iNOS = Inducible nitric oxide synthase; NRF2 = Nuclear factor erythroid 2-related factor 2; BA = Bile acids; EGF = Epidermal growth factor; HGF = Hepatocyte growth factor; HPC = Hepatic progenitor cells; BEC = Biliary epithelial cells; MET = Methionine; BMP = Bone morphogenetic proteins; HNF4 = Hepatocyte nuclear factor 4 alpha; YAP = Yes-associated protein.

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Figure 1. Location of the human liver

Figure 2. Liver anatomy

Figure 3. Liver lobule

Footnote: (a) Cross section of a hepatic lobule. (b) Enlarged longitudinal section of a hepatic lobule. (c) Light micrograph of hepatic lobules in cross section.

Figure 4. Human liver microscopic anatomy

Figure 5. Factors associated with liver regeneration

Abbreviations: PHx = partial hepatectomy; PLTx = partial liver transplantation; EGF = epidermal growth factor; HGF = hepatocyte growth factor; HIF-1α = hypoxia inducible factor 1-alpha; HSCs = hepatic stellate cells; IGF = insulin-like growth factor; IL = interleukin; LSECs = liver sinusoidal endothelial cells; LPCs = liver progenitor cells; LPS = lipopolysaccharide; NO = nitric oxide; PVP = portal vein pressure; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor.

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Types of liver regeneration

Until recently, it was believed that the liver mass after partial hepatectomy or injury recovers via hepatocyte proliferation for 1–2 cell cycles; however, recent studies have shown that different stimuli define the type of liver regeneration that occurs ²⁶. There are two known types of liver regeneration ²⁴:

The first is called Typical liver regeneration that is conducted through the hypertrophy and/or hyperplasia of hepatocytes and biliary epithelial cells. Typical regeneration is specific to a healthy liver that was exposed to resection or an acute liver injury;
The second is called Progenitor-Dependent liver regeneration that requires the reprogramming of specific hepatic cells, whose activation depends on the volume of the residual liver mass. Progenitor-dependent regeneration is specific to chronic liver diseases and massive acute liver injuries ²⁷. Therefore, a 2/3 hepatectomy leads to the immediate hypertrophy of hepatocytes and further hyperplasia, whereas a 1/3 hepatectomy only triggers cell hypertrophy. Various chronic diseases and massive injuries initiate the activation of hepatic progenitor cells, which are responsible for liver regeneration ²⁶. Consequently, typical liver regeneration is driven by mature hepatocytes and biliary epithelial cells, whereas the alternative regeneration method is performed by hepatic progenitor cells ²⁸.

Typical liver regeneration

Partial hepatectomy causes a hemodynamic disturbance, expressed as a portal pressure escalation, which serves as a regeneration stimulus ²⁴. Consequently, hepatocytes, biliary epithelial cells, Ito cells, Kupffer cells and sinusoid endothelial cells are proliferated. Interestingly, hepatocytes proliferate first, whereas biliary epithelial cells start to proliferate only 2-3 days after partial hepatectomy. After a 2/3 partial hepatectomy, the hepatocytes go through one cycle of DNA synthesis, which is required for the restoration of 60% of the liver mass. In the following stages, several but not all hepatocytes continue to proliferate to achieve complete liver recovery. Afterward, apoptotic activity increases with the purpose of correcting an excessive regenerative response ¹³.

Phases of typical liver regeneration

The beginning of each phase is initiated by a certain molecule set released in response to organ damage ²⁹. The earliest regeneration drivers are portal pressure changes and an increasing level of urokinase plasminogen activator (uPA) ³⁰.

Priming phase

During the first phase of regeneration, hepatocytes, driven by various cytokines, simultaneously enter the G1 phase of the cell cycle ²⁷.

The increasing blood pressure in the hepatic sinusoids is conditioned by the incompatibility between the volume of the liver and the volume of inflowing venous blood ³¹, which results in a turbulent flow and mechanically stimulates sinusoid endothelial cells to secrete large amounts of urokinase plasminogen activator (uPA). uPA promotes plasminogen-plasmin transformation, leading to matrix metalloproteinase (MMP) activation and fibrinogen degradation. Plasmin and MMPs are involved in extracellular matrix (ECM) remodeling, resulting in the release of growth factors, such as hepatocyte growth factor (HGF) ³⁰.

Two proinflammatory cytokines are the main mediators of the first phase: Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6); these cytokines are secreted primarily by liver macrophages under the influence of bacterial lipopolysaccharide and the C3a and C5a components of the complement system ³². IL-6 drives the acute phase response and initiates cytoprotection and the proliferation of hepatocytes via the IL-6-IL-6R interaction and the activation of coreceptor glycoprotein 130 (gp130), which activates the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Mitogen-activated protein kinase (MAPK) and PI3K/AKT signaling pathways ³³. Although gp130 is present on the surface of most cells, IL-6R is primarily located on hepatocytes. However, there are also soluble IL-6Rs that initiate the trans-signaling pathway within cells lacking IL-6R and enhance the regenerative response of hepatocytes ³⁴. Fazel Modares et al ³⁵ elicited the crucial role of the trans-signaling pathway in liver regeneration after partial hepatectomy because hepatocyte IL-6R activation alone was not sufficient to initiate cell proliferation. TNF-α has two main functions: It activates the NF-κβ signaling pathway through direct interaction with TNF-R1 on Kupffer cell surfaces and through the indirect induction of inhibitory KB kinase; it also stimulates hepatocyte c-Jun N-terminal kinase (JNK). JNK phosphorylates the c-Jun transcription factor in the nucleus to induce cyclin-dependent kinase 1 transcription, which activates hepatocyte proliferation ³⁰.

The augmenter of liver regeneration (ALR) protein, which has three isoforms (15, 21 and 23 kDa) and is expressed primarily in the liver, testes, kidneys and brain, plays a crucial role in liver regeneration. Each isoform of ALR has a different location within the cell and thus plays a different role ³⁶. For example, mitochondrial long-form ALR translocates proteins and initiates MitoNEEt release, which leads to cell proliferation. Long-form ALR expression increases in cases of pathology and reduces liver damage, protects against oxidative stress and endoplasmic reticulum stress by decreasing Ca++ levels, and has an antimetastatic effect on hepatocellular carcinoma. Cytoplasmic short-form ALR enhances the hepatocyte response to IL-6 by inducing the phosphorylation of STAT3; it also has an antimetastatic effect on hepatoma by inhibiting the migrative and invasive capacity of cells ³⁷. After partial hepatectomy, the ALR concentration increases immediately and activates MAPK signaling; enhances IL-6, TNF-α and inducible nitricoxide synthase production by Kupffer cells; and inhibits NK cell activity. Short-form ALR protects hepatocytes by inhibiting apoptosis stimuli ³⁸.

Proliferative phase

During the second phase of liver regeneration, the G1/M phase transition occurs, which is driven by two groups of mitogens: Complete mitogens, including hepatocyte growth factor (HGF), TGF-α, epidermal growth factor (EGF), and HB-EGF; and the stimulation of DNA synthesis and cell proliferation via Ras-MAPK and PI3K/AKT signaling activation and auxiliary mitogens, including bile acids, vascular endothelial growth factor (VEGF), noradrenalin, insulin-like growth factors (IGFs), estrogen and serotonin ³⁴.

Hepatocyte growth factor (HGF) is produced by mesenchymal liver cells and interacts with the methionine (MET) receptor, leading to PI3K and MAPK signaling protein phosphorylation followed by PI3K/AKT and extracellular-signal-regulated kinase 1/2 signaling activation. This process results in the proliferation, migration, and differentiation of liver cells and antiapoptotic effects ³⁹. Epidermal growth factor receptor (EGFR)-transmembrane receptors with tyrosine kinase activity interact with EGF, TGFa, amphiregulin, epigen, and HB-EGF, leading to MAPK, PI3K/AKT–mammalian target of rapamycin (mTOR) and STAT signaling activation, which drives hepatocyte proliferation ⁴⁰. Natarajan et al ⁴¹ identified impaired liver regenerative capacity and delayed cyclin D1 expression in mice lacking EGFR.

Nuclear factor erythroid 2-related factor 2 (NRF2) transcription factors, which regulate a wide range of genes including antioxidant proteins and detoxifying enzymes, are activated in response to increased reactive oxygen species levels. The expression of this molecule increases in the earliest stages of liver regeneration as a result of cellular damage ⁴². Zou et al ⁴³ discovered the important role of Nrf2 in the regulation of cell cycle progression in mice. Nfr2 is a transcriptional suppressor of Cyclin A2 and a regulator of the Wee1/Cdc2/Cyclin B1 pathway, which controls the beginning of the M phase ⁴³. Nfr2 also regulates hepatocyte proliferation by modulating the insulin/IGF-1 and Notch1 signaling activities and facilitates the capability of hepatocyte nuclear factor 4 alpha (HNF4α) to keep newly formed hepatocytes in a differentiated state ⁴⁴.

Bile acids are the main end products of cholesterol metabolism and are synthesized exclusively in the liver, where they function as signaling molecules that activate membrane G-protein-coupled bile acid receptor 1 (or TGR5) and nuclear farnesoid X receptor (FXR) ⁴⁵. After the loss of liver mass due to partial hepatectomy, the bile acids concentration increases during the first minute, which leads to FXR activation, resulting in inhibited bile acid synthesis and induction of the FOXM1B gene ⁴⁶. FOXM1B is a transcription factor that regulates DNA synthesis and mitosis via cyclin-dependent kinase 2 (CDK2) activation, which is required for the G1/S transition and CDK1 activation and is responsible for the S/M transition ⁴⁷. FXR activation also appears in enterocytes and leads to the induction of fibroblast growth factor (FGF)15/FGF19 expression. The Fgfr4/β-Klotho receptor, which is located on the hepatocyte surface, inhibits BA synthesis and activates the cell cycle via FOXM1B induction when activated ⁴⁸. Fgfr4/β-Klotho activation also regulates the termination of liver regeneration and terminal organ size. Kong et al ⁴⁹ showed that mice with enhanced Fgf15 expression have the most active Hippo signaling pathway, which induces cellular senescence and suppresses transcriptional activation. TGR5, which is located on Kupffer cells, SEC and BEC surfaces, leads to cAMP induction and nuclear factor kappa B (NF-κB)-signaling inhibition ⁵⁰. As a result, decreased proinflammatory cytokine synthesis occurs in Kupffer cellss and bone marrow macrophages via the protein kinase B-dependent activation of the mTOR ⁵¹. TGR5 protects the liver from BA overload by increasing its excretion with urine; it also enhances the secretion of HCO3ˉ and Clˉ and controls BA polarity because inordinately hydrophobic molecules can damage the regenerating liver ⁵².

Wnt ligands are glycoproteins secreted by nonparenchymal liver cells, mostly Kupffer cellss and sinusoid endothelial cells, and are crucial molecules of liver regeneration ⁵³. Wnt ligands lead to the integration of Axin into the cytoplasmic membrane through interaction with the Frizzled receptor and the coreceptors LRP5/6, resulting in impaired function of the β-catenin degradation complex. Therefore, Wnt ligands lead to β-catenin accumulation, followed by its translocation to the nucleus and interaction with members of the transcriptional T cell factor family, resulting in target gene transcription, for example, of cyclin D1, leading to hepatocyte proliferation ⁵⁴. Preziosi et al ⁵⁵ identified the constitutional secretion of Wnt2 and Wnt9b by central vein endotheliocytes and the essential role of these molecules in the basal activation of β-catenin and metabolic zonation of hepatocytes. partial hepatectomy leads to increased Wnt2 and Wnt4 expressions within all zones of the hepatic acinus and the additional secretion of Wnt9b and Wnt5b within the pericentral zone during the first 12 h. This leads to a 7–8-fold increase in cyclin D1 expression within the periportal and intermediate zones and 20-and 100-fold increases in glutamine synthetase expression within the intermediate zone and the pericentral zone, respectively. The role of increased glutamine synthetase expression remains unknown but is thought to be an enhancer of pericentral detoxification since the other 2/3 of hepatocytes restore organ mass ⁵⁵.

The Hedgehog (Hh) signaling pathway is a morphogenic pathway that regulates embryonic development and is implicated in homeostasis maintenance ⁵⁶. Among vertebrates, this pathway is activated within a special organelle, the primary cilium, via the interaction of Hh ligands Sonic hedgehog, Indian hedgehog and Desert hedgehog and the Ptched receptor ⁵⁷. After that, phosphatidylinositol 4-phosphate ⁵⁸, sumoylated molecules and cholesterol ⁵⁹ form a complex with smoothened (Smo), which leads to its activation. Activated Smo dislocates to the apex of the PC and activates Glis (including Gli1, Gli2 and Gli3), which then translate to the nucleus and regulate gene transcription ⁶⁰. The said pathway is canonical, but there are also different types of noncanonical Hh signaling pathways; for example, the Smo-free activation of Glis or the Hh pathway arises beyond the primary cilium ⁶¹. Ochoa et al ⁶² identified a meaningful role of Hh signaling in liver regeneration. partial hepatectomy leads to Hip inhibition, thus activating the Hh pathway via an increase in the Indian hedgehog level in the replicative period and an increase in the Sonic hedgehog level in the postreplicative period. Platelet-derived growth factor, TGF-β, and EGF are secreted in response to liver damage induced by JNK-dependent Hh ligand synthesis ⁶³. Hh signaling activation occurs within hepatocytes, Ito cells ⁶⁴ and biliary epithelial cells ⁶⁵, leading to ECM remodeling, progenitor cell expansion and liver epithelial cell proliferation ⁶⁰. Additionally, Hh signaling controls Yes-associated protein 1 (YAP) of activated Ito cells ⁶⁶. The Hh-YAP signaling pathway induces the glutaminolysis required for Ito cell activation to regulate liver regeneration ⁶⁷. Furthermore, Hh signaling facilitates cell survival via inhibiting hepatocytes, biliary epithelial cells, Ito cells and progenitor cell apoptosis ⁶⁸.

Notch signaling is an important pathway in embryonic development, homeostasis maintenance, and liver regeneration ⁶⁹. Mammals have 4 types of receptors for this pathway (Notch1, Notch2, Notch3, and Notch4); Notch1 and Notch2 are located primarily on biliary epithelial cells and HPCs whereas Notch3 and Notch4 are expressed by the mesenchymal compartment of the liver and are poorly represented on epithelial liver cells. JAG-1 and DLL-4 are ligands of Notch signaling that are expressed in the liver ⁷⁰. The main role of this pathway in liver development is the JAG1-NOTCH2 interaction, which results in the differentiation of hepatoblasts to biliary epithelial cells and the development of the intrahepatic biliary tree ⁷¹. Lu et al ⁷² showed that the role of the Notch–RBPJ interaction is to drive hepatic progenitor cell differentiation to biliary epithelial cells via Yap inactivation after partial hepatectomy in mice. The direction of hepatic progenitor cell differentiation is defined by the balance of NOTCH signaling and Wnt ligands ⁷³. Ortica et al ⁷⁴ pointed out the important role of Notch3 in HPC differentiation to hepatocytes. Zhang et al ⁷⁵ elicited the regulatory role of Notch signaling in hepatocyte proliferation via the NICD/Akt/Hif-1α pathway after partial hepatectomy, whereas its inhibition leads to delayed S phase entry, impaired S phase and M phase progression, and the loss of the hepatocyte mitotic rhythm due to cyclin E1, A2 and B1 dysregulation. Yang et al ⁷⁶ demonstrated the involvement of Notch signaling in the regeneration of 8 types of liver cells, which is performed by the activity of 9 different pathways and regulates cellular proliferation, apoptosis, the cell cycle, etc.

Termination phase

When the needed Liver mass: Body mass ratio is achieved, cellular proliferation stops due to inhibitory molecules that control the rapidity and direction of liver regeneration. Among the inhibitors of cell proliferation, IL-1, which is synthesized by nonparenchymal liver cells, inhibits the DNA synthesis induced by HGF, EGF and TGF-α. IL-6 is multifunctional and plays a role as both a liver regeneration inducer and inhibitor; its effect depends on the time and dose of the molecule. The IL-6-dependent inhibition of proliferation is likely to occur by increasing p21 expression ⁷⁷. The JAK/STAT signaling pathway is inhibited by 8 members of the SOCS family of proteins; hereafter, only SOCS1 and SOCS3 contain the extended SH2 and kinase inhibitory region. SOCS1 directly binds and inhibits JAK, whereas SOCS3 binds to cytokine receptors, forms a complex with JAK and inhibits the STAT3 signaling pathway. SOCS3 is the main suppressor of the signaling pathway activated by IL-6; it inhibits the phosphorylation of coreceptor gp130, JAK and STAT3. SOCS1 negatively regulates the hepatocyte proliferation induced by HGF via c-MET signaling inhibition and likely regulates the TNF-α levels because it interacts with toll-interleukin 1 receptor domain-containing adaptor protein, which drives the synthesis of a current mediator ⁷⁸.

Some TGF-β family members function as inhibitors of proliferation. In particular, TGF-β1 plays a special role in binding to receptor types 1 and 2 and inducing cell apoptosis to correct an excessive liver mass. Outside of the liver, TGF-β1 is synthesized in platelets and the spleen. The spleen might be involved in the termination phase for it inhibits HGF and its c-MET receptor expression. In this regard, splenectomy leads to increased hepatocyte proliferation in the first 48 hour after partial hepatectomy. Other members of the TGF-β family are involved in the termination phase of liver regeneration, including activin A-hepatocyte proliferation inhibitors and bone morphogenetic proteins (BMPs) ³⁴. BMP9 is expressed exclusively by liver tissues and in part by hepatocytes. BMP9 regulates a variety of biological functions such as glucose and lipid metabolism, angiogenesis, oncogenesis, and fibrogenesis, and it affects liver regeneration after acute injuries ⁷⁹. Addante et al ⁸⁰ reported a regulatory function of BMP9 over hepatic progenitor cells that is affected by anaplastic lymphoma kinase 2 type I receptor activation, resulting in SMAD 1, 5, and 8 induction, hepatic progenitor cell apoptosis stimulation, and a reduction in hepatic progenitor cells. Apart from its negative influence on liver regeneration, BMP9 also has profibrogenic activity and promotes hepatocellular carcinoma (HCC) proliferation and invasion. Additionally, BMP9 enhances the expression of TLR4 on the SEC surface, leading to inflammatory cell recruitment. Therapy with anti-BMP-9/ anaplastic lymphoma kinase 1 can potentially enhance hepatocyte proliferation among patients with chronic liver diseases and decrease the probability of fibrosis and HCC development ⁸¹.

HNF4-α regulates hepatocyte differentiation and, according to Huck et al ⁸², promotes the termination of liver regeneration. The expression of the current molecule significantly decreased during the priming phase and increased during the following phases, which is necessary for termination and hepatocyte function recovery after partial hepatectomy ⁸². HNF4-α is a YAP and TGF-β/SMAD3 antagonist; therefore, decreased expression of this molecule stimulates promitogenic functions and activates connective tissue growth factor. Increased HNF4-α expression during the subsequent phases of regeneration prevents the excessive synthesis of connective tissue and therefore fibrosis ⁸³. Hnf4-α also leads to the inhibition of HPC proliferation and migration in rats ⁸⁴.

Integrin-linked kinase is a suppressor of hepatocyte proliferation that is located under the cytoplasmic membrane and is associated with a3/b1 integrins of the ECM. Interruption of this connection results in hepatostat imbalance and excessive liver mass. Focal adhesion kinase is also associated with a3/b1 integrin and promotes hepatocyte proliferation ⁸⁵.

The Hippo signaling pathway is a crucial regulator of the terminal organ size within mammals. The key component of the mammalian Hippo pathway is a kinase cascade in which the Ste20-like kinases 1/2 phosphorylate and activate large tumor suppressor 1/2, its adapter protein Mps one binder 1, and the transcriptional coactivators Yap and Taz ⁸⁶. Phosphorylated Yap and Taz emerge from the nucleus, where they are bound to transcription factors that control the proliferation and differentiation of cells, such as TEAD family members ⁸⁷. The Hippo/Yap signaling pathway is likely an integrator of a large number of alternative growth factor signaling pathways and regulates liver size by balancing negative and positive regulatory signals ⁸⁵. The Hippo signaling pathway does not have any specific receptors and is regulated by molecules that control cellular polarity and morphology, intercellular adhesion and other processes. The activity of this pathway is modulated in response to mechanical deformation and intercellular adhesion defects and cell adhesion to the intercellular matrix. Consequently, Hippo signaling senses cellular and tissue integrity ⁸⁸. Intranuclear Yap is located in periportal hepatocytes and biliary epithelial cells, whereas pericentral hepatocytes contain few current molecules, which is exactly the opposite of the constitutive Wnt ligand content; therefore, current pathways inhibit one another ⁸⁹.

Progenitor-dependent liver regeneration

The mechanisms described above are specific for healthy livers and occur among living liver donors. However, in most cases, liver resection occurs within patients with impaired liver function, and subsequent regeneration proceeds in a nonstandard way, which can lead to hepatic failure and death ⁹⁰. Hepatocytes are the main cells driving typical liver regeneration, whereas alternative liver regeneration is performed by hepatic progenitor cells (HPCs) ⁹¹. The process of progenitor-dependent liver regeneration is shown in Figure 6 below.

Acute liver failure caused by intoxication, viral hepatitis A, B or E, autoimmune liver disease, etc., is often followed by widespread necrotic and apoptotic zones, and adequate liver regeneration becomes impossible ⁹². During acute liver failure, the main regenerative role is given to hepatic progenitor cells, as indicated by the increased level of alpha-fetoprotein (AFP). Therefore, a high AFP level is correlated with a positive prognosis after acetaminophen-induced liver damage ¹³. The immune system regulates liver regeneration via necrotic cell phagocytosis and controls inflammatory reactions in response to injury. The number of proliferative macrophages in the liver significantly increases after organ damage, and monocytes are recruited from the bloodstream and differentiate into macrophages in response to increasing the colony-stimulating factor 1 levels. Colony-stimulating factor 1 injection promotes liver regeneration after partial hepatectomy; conversely, a low level of the current factor is correlated with a negative patient prognosis ²⁸.

Liver steatosis is associated with an impaired regenerative function, in which GADD34 plays an important role since its increased expression promotes liver regeneration within mice. Ischemia-reperfusion injury often complicates the posttransplantation period and impairs typical liver regeneration. The current complication is followed by increased receptor for advanced glycation end product levels, which might be a therapeutic target. Thus, receptor for advanced glycation end product inhibitor injection leads to a reduction in organ damage and the induction of liver regeneration. The excessive synthesis of extracellular matrix components by activated hepatic stellate cells (Ito cells) inhibits hepatocyte proliferation, and if macrophage matrix metalloproteinases do not promote connective tissue restitution, the angioarchitecture of hepatic lobules is impaired, resulting in cirrhosis ⁹². In the liver, damage due to cirrhosis and hepatitis B or C often reveals hepatocytes with biliary epithelial cell markers, such as epithelial cell adhesion molecule (EpCAM), on their surface. The presence of these intermediate hepatobiliary cells is thought to be explained by their origin from biliary compartment progenitors ⁸.

Figure 6. Progenitor-dependent liver regeneration

Footnote: In case of excessive acute injury or chronic liver diseases, hepatic progenitor cell activation occurs in response to different inflammatory cytokines, including tumor necrosis factor-like weak inducer of apoptosis. Depending on the type of stimulus, hepatic progenitor cells can differentiate into biliary epithelial cells or hepatocytes to restore the liver mass.

Abbreviations: PV = Portal vein; HA = Hepatic artery; CV = Central vein; BECs = Biliary epithelial cells; HPCs = Hepatic progenitor cells; HNFs = Hepatocyte nuclear factors.

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Biomarkers for liver regeneration

Colony stimulating factor 1 (CSF1) was measured in serum samples from 55 patients after hepatic resection and 78 patients with acetaminophen overdose acute liver failure ⁹³. Serum CSF1 levels increased in patients with hepatic resection in proportion to the resected liver volume, and a low serum CSF1 level was associated with worse prognosis (King’s College criteria) and increased mortality/transplantation in patients with acetaminophen overdose acute liver failure. Serum CSF1 level was a better predictor than HMGB1 released by necrotic cells and proposed as a prognostic marker for acute liver failure ⁹⁴. Furthermore, as subcutaneous CSF1-Fc administration promoted the macrophage accumulation and liver regeneration in mice with acetaminophen acute liver injury ⁹⁴, CSF1 could be not only a prognostic marker, but also a therapeutic target for liver regeneration in acute liver injury. Recombinant human macrophage-CSF was apparently well tolerated in humans ⁹⁵.

The microRNAs mediate both activation and inhibition of gene expression at the posttranscriptional or translational levels, and affect biological pathways including cellular differentiation, proliferation, apoptosis, and tissue remodeling ⁹⁶. Recently, microRNAs have been demonstrated to regulate cell proliferation during liver regeneration, and to serve as putative therapeutic targets for liver regeneration ⁹⁷. Patients with spontaneous recovery from acute liver failure showed significantly higher serum levels of microRNA-122, microRNA-21, and microRNA-221, compared to non-recovered patient cohort ⁹⁸. The elevated microRNAs serum levels were accompanied with down-regulation of growth inhibitory targets in the liver tissue, such as heme oxygenase-1, programmed cell death 4, and the cyclin-dependent kinase inhibitors p21, p27, and p57, as well as increased cyclin D1 expression and hepatocyte proliferation. Thus, microRNA-122, microRNA-21, and microRNA-221 involved in liver regeneration might also serve as a biomarker to predict acute liver failure ⁹⁹.

Above all, most simple and available marker suggesting liver regeneration is alpha-fetoprotein (AFP). AFP is also known as a hepatic progenitor-associated marker besides a representative marker of hepatocellular carcinoma ¹⁰⁰. In a prospective study of 206 patients, the AFP ratio (AFP concentration at day 3 of admission divided by that at day 1) ≥1 predicted the survival of acute liver failure patients ¹⁰¹. Rising AFP levels over the first 3 hospital stay days might indicate a better survival rate.

What helps the liver regenerate?

Liver regeneration is a highly orchestrated process influenced by various factors, with many aspects of liver regeneration still not understood ²⁴ and the mode of liver regeneration is influenced by the amount of liver resection ⁵. Liver regeneration is a complex process regulated by the interaction between growth factors and cytokines secreted near the site of injury or transferred to the liver by the blood. This strictly orchestrated process is divided into 3 phases: Priming, proliferation, and termination ¹⁰². The sum of all signals that sense the physiologically necessary liver mass is called the “hepatostat”, which can initiate and terminate liver regeneration ¹⁰³. This phenomenon reflects the correlation between the needs of organisms and the organ mass that is required for homeostasis ¹⁰⁴.

Therapeutic methods for insufficient liver regeneration treatment are lacking, although many studies have focused on the efficiency of various molecules in promoting liver regeneration ²⁴. Further studies in this field can help determine how to prevent liver failure after surgical interventions and acute and chronic injuries via improving liver regeneration. Shi et al ¹⁰⁵ determined that baicalin can stimulate liver regeneration after acetaminophen-induced acute liver injury in mice via inducing hepatocyte proliferating cell nuclear antigen, increasing cyclin D1 expression and Nrf2 cytosolic accumulation, and enhancing IL-18 Levels, leading to the upregulation of hepatocyte proliferation. So et al ¹⁰⁶ showed the promotion of liver regeneration after the inhibition of EGFR or MEK/extracellular signal-regulated kinase (ERK) and the genetic suppression of the EGFR-ERK-SOX9 axis via inducing HPC-to-hepatocyte differentiation in zebrafish. The research of Xiang et al ¹⁰⁷ noted the therapeutic effect of IL-22Fc in inducing liver regeneration in acute-on-chronic liver failure patients due to the shift from anti-regenerative IFN-γ/STAT1 to the pro-regenerative IL-6/STAT3 pathway. Li et al ¹⁰⁸ reported that aldose reductase is a new potential therapeutic target for enhancing normal and fatty liver regeneration after surgery and ischemia-reperfusion injury because the knockout of aldose reductase leads to enhanced oxisome proliferator activated receptor-α and oxisome proliferator activated receptor-γ expression, thus improving energy metabolism in the liver. The research of Loforese et al ¹⁰⁹ revealed that the inhibition of MST1 and MST2 with si-RNA resulted in improved hepatocyte proliferation in aged mice after partial hepatectomy; therefore, Ste20-like kinases 1/2 may be a potential therapeutic target. Many other molecules and molecular pathways have been shown to enhance liver regeneration in experimental models. Further studies would help implicate the potential therapy in the clinic and improve the survival of patients with different liver diseases in the near future.

Mesenchymal stem cells (MSCs) have a self-renewal capacity and are derived from the bone marrow, adipose tissue, umbilical cord, etc. They are the subject of focus in regenerative medicine and serve as a potential therapy for different liver diseases ¹¹⁰, ¹¹¹. Mesenchymal stem cells were shown to improve liver regeneration in patients with cirrhosis by elevating anti-apoptotic factors, such as HGF and IGF-1, and angiogenic and mitogenic factors. In acute liver failure animal models, mesenchymal stem cells have been shown to promote liver regeneration mostly by suppressing the oxidative stress and inflammation via reducing TNF-α, IFN-γ and IL-4 Levels and stimulating liver regeneration with various released factors such as PGE2 and delta-like 4 ¹¹², ¹¹³. Mesenchymal stem cells can also stimulate liver regeneration after partial hepatectomy by upregulating hepatic cell proliferation and downregulating fat accumulation and hepatocyte growth factor (HGF), IL-6, IL-10 and TNF-α serum levels ¹¹⁴.

Table 2. Possible targets and roles in liver regeneration for acute severe injury

				Application to severe liver injury
Role in liver regeneration	Targets	Animal study	Human study (evidence in liver regeneration)	Prevention of acute liver failure following small-for-size syndrome	Ongoing acute liver failure or extensive hepatocyte injury	References
Promotion	PVE, ALPPS, two-stage hepatectomy	Yes	Yes (Clinically standard technique)	Yes	N/A	¹¹⁵
	Modulation of portal flow	Yes	Yes (Retospective study, beneficial)	Yes	N/A	¹¹⁶
	Pentoxifylline	Yes	Yes (Randomized controlled clinical trial, beneficial)	Yes	N/A	¹¹⁷
	Omega-3 fatty acid	Yes	Yes (Randomized controlled clinical trial, beneficial)	Yes	N/A	¹¹⁸
	Platelet, serotonin	Yes	Yes (Prospective observational study, beneficial)	Yes	N/A	¹¹⁹
	G-CSF	Yes	Yes (Randomized controlled clinical trial, beneficial)	N/A	Yes	¹²⁰
	FXR agonist, FGF19 analogue	Yes	No	Yes	N/A	¹²¹
	RAGE inhibitor	Yes	No	Yes	N/A	¹²²
	TGFβR1 inhibitor	Yes	No	N/A	Yes	¹²³
	mTORC1 inhibitor (Autophagy inducer)	No	No	N/A	N/A	¹²⁴
Inhibition	Steatosis	Yes	Yes (Equivocal due to inaccuracy of diagnosis)			¹²⁵
	Fibrosis	Yes	Yes (Equivocal due to inaccuracy of diagnosis)	Risk factors		¹²⁶
	Aged liver	Yes	Yes (Retrospective study, injurious)	Risk factors		¹²⁷
	Cholangitis	Yes	Yes (Retrospective study, injurious)			¹²⁸
Support (Alternation)	Bioartificial liver	Yes	Yes (Randomized controlled clinical trial, no beneficial)	N/A	Yes	¹²⁹
	Cell transplantation	Yes	Yes (Case series, limited beneficial)	N/A	Yes	¹³⁰
	Organ engineering	Yes	No	N/A	Yes	¹³¹

Abbreviations: ALF = acute liver failure, ALPPS = associating liver partition and portal vein ligation for staged hepatectomy; BAL = bioartificial liver; FGF = fibroblast growth factor; FXR = farnesoid X nuclear receptor; G-CSF = granulocyte colony-stimulating factor; mTORC1 = mammalian target of rapamycin complex 1; N/A = not available; PVE = portal vein embolization; RAGE = receptor for advanced glycation end products; RCT = randomized controlled clinical trial; SFSS = small-for-size syndrome; TGFβR1 = transforming growth factor beta receptor 1

[Source ⁹⁹ ]

Pentoxifylline

The effects of pentoxifylline, which enhances production of interleukin (IL)-6 while inhibiting the TNFα, were evaluated in 101 non-cirrhotic patients undergoing major hepatectomy ¹¹⁷. Continuous intravenous administration of pentoxifylline, starting 12 hours before and ending 72 hours after the surgery, resulted in significantly higher regeneration volume for small liver (remnant liver to body weight ratio ≤ 1.2%) and stronger induction of interleukin-6 (IL-6) mRNA levels. This study suggested the beneficial effects of pentoxifylline on liver regeneration in small remnant livers, mediated by IL-6 production ⁹⁹. Perioperative treatment with pentoxifylline might enhance liver regeneration following major hepatic resection.

Omega-3 fatty acids

Omega-3 fatty acids nutrition for 7 days after the surgery was reported to mitigate liver injury, reduce infection morbidities, and shorten the post-hospital stay in patients receiving liver transplantation ¹³². Another clinical study ¹¹⁸ showed that liver regeneration calculated with volume factors was significantly increased in patients receiving omega-3 fatty acids enriched lipid emulsion for 3 days (2 days before surgery and postoperative day 0) compared with controls after hepatic resection. Experimentally, polyunsaturated fatty acids (PUFAs) administration enhanced expression of the liver kinase B1-adenosine monophosphate-activated protein kinase (LKB1-AMPK) signaling pathway after 70% partial hepatectomy in rats, leading to improved integrity of tight junctions and hepatocellular function ¹³³. LKB1 was necessary in the phosphorylation of Akt downstream targets, including FoxO3a and glycogen synthase kinase 3β (GSK3β) ¹³⁴. As AMPK activation stimulates the transport from nucleus to cytoplasm of Hu antigen R (HuR), which is an RNA-binding protein that increases the half-life of target mRNA involved in cell cycle progression ¹³⁵, the deletion of AMPKα1 was reported to delay liver regeneration ¹³⁶. Clinical and experimental studies suggest that omega-3 fatty acids might promote liver regeneration through the LKB1 and AMPK activation even despite a short term administration.

Resveratrol

Studies suggest that the bioactive polyphenolic compound resveratrol, found naturally in certain foods such as red grapes and peanuts, may be able to ameliorate liver damage ¹³⁷. However, the effects and efficacy of long-term treatment with resveratrol remain unclear. In an experiment involving C56BL/6 mice, scientists use acetaminophen (acetaminophen; 400 mg/kg/day for 15 days) overdose model to induce liver. Three days after the intoxication was stopped, they observed biochemical, histological and ultrastructural alterations in the livers of these mice. The acetaminophen-treated animals were then given resveratrol (10 mg/kg/day) for 60 days. Blood and tissue were analyzed at days 7, 30 and 60. The data showed that long-term resveratrol treatment (60 days) ameliorates the liver injury caused by acetaminophen intoxication, restoring histological features, ultrastructural organization and serum biochemical parameters (albumin, alanine aminotransferase) ¹³⁷. Ck18- and F4/80-positive cells (indicators of hepatocyte recovery) were reestablished and the number of α-SMA positive cells was normalized after long-term resveratrol treatment ¹³⁷. Additionally, downregulation of the drug transporter BCRP (Breast Cancer Resistance Protein) was observed. Electron microscopy revealed that treatment with resveratrol was effective in restoring the shape and size of hepatic microvilli and normalizing both the number and viability of mitochondria. Taken together, these results indicate that long-term treatment with resveratrol is effective in alleviating liver injury caused by acetaminophen administration.

Platelets and serotonin

A recent study ¹¹⁹ evaluated the effects of intra-platelet serotonin on liver regeneration and oncologic outcome in 96 patients. This study demonstrated that patients with preoperative high intra-platelet serotonin levels exhibited a significant reduction in liver dysfunction after hepatic resection for malignant tumors. On the other hand, these patients suffered from a high incidence of postoperative tumor recurrence ¹¹⁹. In addition, patients receiving perioperative selective serotonin reuptake inhibitor (SSRI) treatment, which effectively reduced the intra-platelet serotonin levels, displayed a substantial increase in postoperative morbidities and had no tumor recurrence within 12 months after the surgery. This study suggested the potential of serotonin in both liver regeneration and tumor growth. Induction of thrombocytosis drives liver regeneration, while inhibition of platelet aggregation or reduction of platelet number impairs liver regeneration in mice after partial hepatectomy ¹³⁸. It has been commonly conceived that release of platelet granule contents including serotonin and other growth factors, such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF-1) may enhance liver regeneration. A recent study demonstrated that pro- and anti-regenerative proteins in the granules of platelet were selectively released upon activation and were involved in liver regeneration ¹³⁹. However, the role of platelet in liver regeneration has not been fully elucidated. It is also controversial whether serotonin may directly exert mitogenic activity on hepatocytes or indirectly influences liver regeneration through platelet activation. It has been suggested that the role of serotonin on tumor growth is concentration-dependent; while high serotonin dose stimulates tumor growth, low doses of serotonin can inhibit tumor growth by decreasing blood supply ¹⁴⁰. Although it is unclear which factors contribute to liver regeneration, the increase of platelet and serotonin levels might promote liver regeneration. Of note, mitogenic activity of serotonin should be carefully considered in patients with carcinoma ¹¹⁹.

Granulocyte colony-stimulating factor (G-CSF)

A randomized controlled clinical trial ¹⁴¹ evaluated the impact of granulocyte colony-stimulating factor (G-CSF) on liver regeneration in 47 consecutive patients with acute-on-chronic liver failure. Twelve doses of subcutaneous G-CSF, starting within 48 hours of admission, significantly improved patient survival in addition to Child-Pugh score, Model for End-Stage Liver Disease (MELD), and Sequential Organ Failure Assessment (SOFA), which all relate to severity (acuity) of the liver disease ¹⁴¹. As a matter of course, neutrophil counts were higher in G-CSF treated patient cohort. A recent experimental study in mice with acetaminophen-induced acute liver injury demonstrated that neutrophil infiltration was involved not only in injury amplification at the early phase, but also during liver-tissue repair at the later phase ¹²⁰. The administration of matrix metalloproteinases (MMP) inhibitor in those mice successfully ameliorated hepatic damage and mitigated local inflammation along with reduction of neutrophil migration into the liver. However, matrix metalloproteinases (MMP) inhibitor impaired liver tissue repair and function restoration at later time points. Neutrophils seem to contribute to tissue regeneration through the various mechanisms, such as MMP delivery ¹⁴². By regulating neutrophil function, G-CSF is a promising new therapeutic agent for hepatocellular regeneration after severe liver injury.

Farnesoid X nuclear receptor (FXR) agonist and FGF19 analogue

Although there is no evidence of Farnesoid X nuclear receptor (FXR) agonist or fibroblast growth factor-19 (FGF19) analogue to affect acute liver failure in humans, these are attractive therapeutic targets for liver regeneration ⁹⁹. Patients without biliary drainage had significantly higher serum bile acids levels and regenerated liver volumes than patients with biliary drainage after major hepatectomy ¹⁴³. Bile acids drive liver growth by activating their receptor FXR, and are involved in the maintenance of normal liver size through the regulation of fibroblast growth factor (FGF)15 in mice and FGF19 in humans. FGF15/19 binding to FGF receptor (FGFR) 4 on hepatocytes negatively regulates bile acids synthesis with suppression of CYP7A1 ¹⁴⁴. Mice with humanized livers, without normal FGF15/19 regulation, demonstrate increased bile acids levels, ultimately leading to hepatocyte proliferation and enlarged liver size ¹⁴⁵. Inhibition of FXR or FGFR4 signaling was reported to impair hepatocyte proliferation due to reduction of the downstream forkhead box protein M1 (FoxM1) and signal transducer and activator of transcription 3 (STAT3) after PHx in mice ¹⁴⁶. In marked contrast, activating FXR enhances hepatocyte proliferation. Oral administration of obeticholic acid, a potent FXR activator, promoted liver regeneration after portal vein embolization in a rabbit model ¹²¹. FGF19 conjugated to apolipoprotein A-I to increase half-life of FGF19 in circulation, successfully reduced liver steatosis and improved the liver regeneration after partial hepatectomy in obese mice ¹⁴⁷. Thus, FXR and FGF19 analogue have been reported to promote liver regeneration in animal models. The therapeutic effects of FXR agonist and FGF19 analogue in humans have been studied for nonalcoholic steatohepatitis, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) ¹⁴⁸. It might be worth investigating whether FXR agonist or FGF19 analogue impacts on liver regeneration in humans, with obeticholic acid being a good candidate to support liver enlargement after portal vein embolization.

Receptor for advanced glycation end products (RAGE)

The levels of soluble receptor for advanced glycation end products (sRAGE) and RAGE ligands including high mobility group box-1 (HMGB1) were significantly higher in 60 patients with acetaminophen-related acute liver failure as compared with 30 normal controls ¹²². In those 60 patients with acetaminophen-related acute liver failure, soluble receptor for advanced glycation end products (sRAGE) levels were significantly higher in 30 patients who underwent liver transplantation and/or died as compared with 30 spontaneous survivors. In mouse studies, blockage of RAGE signaling using sRAGE reduced hepatocyte apoptosis and increased liver regeneration in both hepatic ischemia and partial hepatectomy models ¹²². Receptor for advanced glycation end products (RAGE) in liver remnants was up-regulated in mice with 85% partial hepatectomy as compared with 70% partial hepatectomy and sRAGE therapy increased the survival of 85% partial hepatectomy mice from 30% to 90% ¹⁴⁹. While soluble receptor for advanced glycation end products (sRAGE) suppresses ligand-induced stimulation of RAGE serving as a decoy receptor, which binds ligands of RAGE competitively, sRAGE seems to be associated with severity of liver injury in humans. Another experimental study using mice demonstrated that angiotensin II receptor antagonist, losartan mitigated ischemia-reperfusion injury through peroxisome proliferator-activated receptor γ (PPAR-γ) activation, which inhibited RAGE signaling ¹⁵⁰. Further studies are required to make the RAGE signaling clinically relevant in liver regeneration.

Transforming growth factor beta receptor 1 (TGFβR1) inhibitor

This study ¹²³ demonstrated that administration of transforming growth factor beta receptor 1 (TGFβR1) inhibitor after 12 hours of acetaminophen-induced acute liver injury mitigated senescence induction, increased hepatocyte proliferation, and reduced jaundice in mice. As TGFβR1 inhibitor has been already evaluated for hepatocellular carcinoma in humans ¹⁵¹, its application as a novel therapeutic strategy to stimulate liver regeneration and reduce hepatocyte senescence in acute severe injury may be possible in the future.

What foods help regenerate the liver?

After your liver transplant, it is especially important to eat a healthy, well-balanced diet to help you recover and keep your liver healthy ¹⁵². A dietitian or nutritionist can help you create a healthy eating plan that meets your nutrition and diet needs. In general, your diet after liver transplant should be low in salt, cholesterol, fat and sugar. To prevent damaging your liver, it’s important to avoid alcohol and cigarettes. Do not drink alcoholic beverages or use alcohol in cooking.

Your dietitian will also provide you with several healthy food options and ideas to use in your nutrition plan. Your dietitian’s recommendations may include:

Eating at least five servings of fruits and vegetables each day
Avoiding grapefruit and grapefruit juice because of their effect on a group of immunosuppression medications
Having enough fiber in your daily diet
Choosing whole-grain foods over processed ones
Drinking low-fat or fat-free dairy products, which is important to maintain optimal calcium and phosphorus levels

Your dietitian may also recommend:

Eating lean meats, poultry and fish
Following food safety guidelines
Staying hydrated by drinking adequate water and other fluids each day

You should avoid consuming the following:

water from lakes and rivers
unpasteurized milk products
raw or undercooked
- eggs
- meats, particularly pork and poultry
- fish and other seafood.

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Human liver regeneration

Human liver regeneration