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Liver Regeneration in Chronic Liver Injuries: Basic and Clinical Applications Focusing on Macrophages and Natural Killer Cells

  • Author Footnotes
    ∗ Authors share co-first authorship
    Yihan Qian
    Footnotes
    ∗ Authors share co-first authorship
    Affiliations
    Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Author Footnotes
    ∗ Authors share co-first authorship
    Zhi Shang
    Footnotes
    ∗ Authors share co-first authorship
    Affiliations
    Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Yueqiu Gao
    Affiliations
    Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Hailong Wu
    Correspondence
    Wu Hailong.
    Affiliations
    Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
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  • Xiaoni Kong
    Correspondence
    Correspondence Address correspondence to: Kong Xiaoni, PhD, Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, 528 Zhangheng Road, Shanghai, China 201203. fax: XXX.
    Affiliations
    Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Author Footnotes
    ∗ Authors share co-first authorship
Open AccessPublished:June 19, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.05.014

      Background & Aims

      Liver regeneration is a necessary but complex process involving multiple cell types besides hepatocytes. Mechanisms underlying liver regeneration after partial hepatectomy and acute liver injury have been well-described. However, in patients with chronic and severe liver injury, the remnant liver cannot completely restore the liver mass and function, thereby involving liver progenitor-like cells (LPLCs) and various immune cells.

      Results

      Macrophages are beneficial to LPLCs proliferation and the differentiation of LPLCs to hepatocytes. Also, cells expressing natural killer (NK) cell markers have been studied in promoting both liver injury and liver regeneration. NK cells can promote LPLC-induced liver regeneration, but the excessive activation of hepatic NK cells may lead to high serum levels of interferon-γ, thus inhibiting liver regeneration.

      Conclusions

      This review summarizes the recent research on 2 important innate immune cells, macrophages and NK cells, in LPLC-induced liver regeneration and the mechanisms of liver regeneration during chronic liver injury, as well as the latest macrophage- and NK cell-based therapies for chronic liver injury. These novel findings can further help identify new treatments for chronic liver injury, saving patients from the pain of liver transplantations.

      Keywords

      Abbreviations used in this paper:

      ALI (acute liver injury), BEC (biliary epithelial cell), BMDM (bone marrow-derived macrophage), FGF (fibroblast growth factor), Fn14 (fibroblast growth factor-inducible 14), HGF (hepatocyte growth factor), Hh (hedgehog), HSC (hepatic stellate cell), HybHP (hybrid hepatocytes), IFN (interferon), IL (interleukin), MH (mature hepatocyte), natural killer (natural killer), NKT cells (cells expressing NK and T-cell markers), PHx (partial hepatectomy), PTEN (phosphatase and tensin homolog), TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), TWEAK (tumor necrosis factor-like weak apoptosis inducing factor)
      This review summarizes the role of macrophages and NK cells in liver progenitor-like cell (LPLC)-induced liver regeneration during chronic liver injuries. Macrophages are beneficial to the proliferation and differentiation of LPLCs. NK cells can promote LPLC-induced liver regeneration, but overactivation may lead to high serum levels of IFN-γ, thus inhibiting liver regeneration.
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      ,
      • Carpino G.
      • Nobili V.
      • Renzi A.
      • De Stefanis C.
      • Stronati L.
      • Franchitto A.
      • Alisi A.
      • Onori P.
      • De Vito R.
      • Alpini G.
      • Gaudio E.
      Macrophage activation in pediatric nonalcoholic fatty liver disease (NAFLD) correlates with hepatic progenitor cell response via Wnt3a Pathway.
      With its direct influence on LPLCs, Wnt3a secreted from macrophages can promote the differentiation toward hepatocytes.
      Other pathways involved in the activation and expansion of LPLCs have also been researched, including thyroid hormone signaling,
      • Bockhorn M.
      • Frilling A.
      • Benkö T.
      • Best J.
      • Sheu S.Y.
      • Trippler M.
      • Schlaak J.F.
      • Broelsch C.E.
      Tri-iodothyronine as a stimulator of liver regeneration after partial and subtotal hepatectomy.
      ,
      • László V.
      • Dezső K.
      • Baghy K.
      • Papp V.
      • Kovalszky I.
      • Sáfrány G.
      • Thorgeirsson S.S.
      • Nagy P.
      • Paku S.
      Triiodothyronine accelerates differentiation of rat liver progenitor cells into hepatocytes.
      HIPPO/YAP pathway,
      • Konishi T.
      • Schuster R.M.
      • Lentsch A.B.
      Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury.
      • Lu L.
      • Finegold M.J.
      • Johnson R.L.
      Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration.
      • Moya I.M.
      • Halder G.
      Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine.
      • Planas-Paz L.
      • Sun T.
      • Pikiolek M.
      • Cochran N.R.
      • Bergling S.
      • Orsini V.
      • Yang Z.
      • Sigoillot F.
      • Jetzer J.
      • Syed M.
      • Neri M.
      • Schuierer S.
      • Morelli L.
      • Hoppe P.S.
      • Schwarzer W.
      • Cobos C.M.
      • Alford J.L.
      • Zhang L.
      • Cuttat R.
      • Waldt A.
      • Carballido-Perrig N.
      • Nigsch F.
      • Kinzel B.
      • Nicholson T.B.
      • Yang Y.
      • Mao X.
      • Terracciano L.M.
      • Russ C.
      • Reece-Hoyes J.S.
      • Gubser Keller C.
      • Sailer A.W.
      • Bouwmeester T.
      • Greenbaum L.E.
      • Lugus J.J.
      • Cong F.
      • McAllister G.
      • Hoffman G.R.
      • Roma G.
      • Tchorz J.S.
      YAP, but not RSPO-LGR4/5, signaling in biliary epithelial cells promotes a ductular reaction in response to liver injury.
      and Jag1/Notch signaling.
      • Ortica S.
      • Tarantino N.
      • Aulner N.
      • Israël A.
      • Gupta-Rossi N.
      The 4 Notch receptors play distinct and antagonistic roles in the proliferation and hepatocytic differentiation of liver progenitors.
      • Lu J.
      • Zhou Y.
      • Hu T.
      • Zhang H.
      • Shen M.
      • Cheng P.
      • Dai W.
      • Wang F.
      • Chen K.
      • Zhang Y.
      • Wang C.
      • Li J.
      • Zheng Y.
      • Yang J.
      • Zhu R.
      • Wang J.
      • Lu W.
      • Zhang H.
      • Wang J.
      • Xia Y.
      • De Assuncao T.M.
      • Jalan-Sakrikar N.
      • Huebert R.C.
      • Zhou Bin
      • Guo C.
      Notch signaling coordinates progenitor cell-mediated biliary regeneration following partial hepatectomy.
      • Zhang F.
      • Zhang J.
      • Li X.
      • Li B.
      • Tao K.
      • Yue S.
      Notch signaling pathway regulates cell cycle in proliferating hepatocytes involved in liver regeneration: the Notch signaling pathway.
      • Yang X.
      • He C.
      • Zhu L.
      • Zhao W.
      • Li S.
      • Xia C.
      • Xu C.
      Comparative analysis of regulatory role of Notch signaling pathway in 8 types liver cell during liver regeneration.
      The various roles of above-mentioned pathways in LPLC initiation and proliferation are summarized in Figure 1.
      Figure thumbnail gr1
      Figure 1Activation, expansion, and differentiation of LPLCs. During chronic liver injuries, dying hepatocytes generate Hh ligands, which not only directly activate LPLC-induced liver regeneration but also indirectly enhance the proliferation of LPLCs by activating HSCs into matrix-producing myofibroblasts. Also, LTβR on HSCs (activated via HIPPO/YAP pathway) may be involved in paracrine signaling with nearby LTβ-expressing LPLCs. After initiation, TWEAK has a selective mitogenic effect for LPLCs, stimulating the proliferation of LPLCs through its receptor Fn14. The stimulation of TWEAK will lead to the activation of NF-κB and proliferation of LPLCs. FGF not only activates the proliferation of LPLCs (FGF7) but also induces the differentiation of LPLCs into hepatocytes (FGF9). HGF/c-met signaling, Wnt/β-catenin signaling, and thyroid hormone signaling are all proved to promote the differentiation of LPLCs into MHs, whereas Jag1/Notch signaling can induce LPLCs differentiating into BECs. BECs, biliary epithelial cells; FGF, fibroblast growth factor; Fn14, fibroblast growth factor-inducible 14; HGF, hepatic growth factor; Hh ligands, hedgehog ligands; HSCs, hepatic stellate cells; LPLCs, liver progenitor-like cells; LTβR, lymphotoxin β receptor; MHs, mature hepatocytes; NF-κB, nuclear factor kappa B; TWEAK, tumor necrosis factor-like weak apoptosis inducing factor; YAP, Yes-associated protein.

      Macrophage in Liver Progenitor-Like Cell–Induced Liver Regeneration

      Because inflammation has been demonstrated to initiate tissue repair by elimination of the causes of injury such as infectious agents and necrotic cells,
      • Campos G.
      • Schmidt-Heck W.
      • Ghallab A.
      • Rochlitz K.
      • Pütter L.
      • Medinas D.B.
      • Hetz C.
      • Widera A.
      • Cadenas C.
      • Begher-Tibbe B.
      • Reif R.
      • Günther G.
      • Sachinidis A.
      • Hengstler J.G.
      • Godoy P.
      The transcription factor CHOP, a central component of the transcriptional regulatory network induced upon CCl4 intoxication in mouse liver, is not a critical mediator of hepatotoxicity.
      ,
      • Karin M.
      • Clevers H.
      Reparative inflammation takes charge of tissue regeneration.
      increasing number of studies have been carried out to identify the roles of immune cells in chronic liver injury-induced liver regeneration (Figure 2). In response to liver injury, liver tissues may initiate the activation of various immune cells, among which the macrophages play a predominant role. In addition to the liver-resident macrophages, also named Kupffer cells, which represent nearly 20% of the liver nonparenchymal cells, hepatic macrophages may also be derived from infiltrating blood monocytes.
      • Epelman S.
      • Lavine K.J.
      • Randolph G.J.
      Origin and functions of tissue macrophages.
      ,
      • Wang M.
      • You Q.
      • Lor K.
      • Chen F.
      • Gao B.
      • Ju C.
      Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice.
      As the immune barrier of liver tissue, Kupffer cells can influence other immune cells through complex cell-cell interactions and secretion of cytokines.
      • Fernández V.
      • Reyes S.
      • Bravo S.
      • Sepúlveda R.
      • Romanque P.
      • Santander G.
      • Castillo I.
      • Varela P.
      • Tapia G.
      • Videla L.A.
      Involvement of Kupffer cell-dependent signaling in T3-induced hepatocyte proliferation in vivo.
      Figure thumbnail gr2
      Figure 2The role of macrophages and NK cells in LPLC-induced regeneration. Macrophages can not only promote the proliferation of LPLCs through TWEAK signaling but also induce the differentiation of LPLCs into hepatocytes via Wnt3a pathway. Ly-6Chigh monocytes will promote tissue injury by secreting IL-1β, IL-6, and IL-12, whereas Ly-6Clow monocytes can suppress inflammation and facilitate liver repair by secreting IL-10, TGFβ1, IL-4, IL-13, and VEGFα. LPLCs can induce the recruitment of infiltrating macrophages to the damaged liver through CCL2/CCR2 and CX3CL1/CX3CR1. Macrophages can also influence other immune cells, including NK cells, through complex cell-cell interactions and secretion of cytokines. NK cells play a beneficial role in LPLCs proliferation, and CXCL7 secreted by NK cells can induce the recruitment of mesenchymal stem cells, thereby improving liver regeneration. Also, IL-22 produced by NK cells and NKT cells can increase HSCs senescence via STAT3 activation, thus alleviating liver fibrosis. CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif chemokine receptor 2; CXCL7, C-X-C motif chemokine ligand 7; CX3CL1, C-X3-C motif chemokine ligand 1; CX3CR1, C-X3-C motif chemokine receptor 1; IFN-γ, interferon γ; IL, interleukin; LPS, lipopolysaccharides; NK cell, natural killer cell; STAT3, signal transducer and activator of transcription 3; TGFβ1, transforming growth factor β-1; TNFα, tumor necrosis factor α; VEGFα, vascular endothelial growth factor α.
      Macrophages influence both the proliferation and differentiation of LPLCs. Kupffer cells or infiltrating macrophages are believed to be the source of endogenous TWEAK.
      • Wiley S.R.
      • Winkles J.A.
      TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor.
      ,
      • Campbell S.
      The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity.
      A direct link has been proved between macrophage TWEAK production and paracrine signaling associated with DRs, leading to the expansion of LPLCs in TWEAK/Fn14-/- mice model.
      • Bird T.G.
      • Lu W.Y.
      • Boulter L.
      • Gordon-Keylock S.
      • Ridgway R.A.
      • Williams M.J.
      • Taube J.
      • Thomas J.A.
      • Wojtacha D.
      • Gambardella A.
      • Sansom O.J.
      • Iredale J.P.
      • Forbes S.J.
      Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling.
      In addition to the TWEAK signaling, macrophages are also associated with Wnt and Notch signaling, thus playing a crucial role in the differentiation of LPLCs into hepatocytes. Wnt3a has been proved to be expressed by macrophages as a result of the phagocytosis of biological debris, implicating the influence of macrophages on environmental sensing and correction of epithelial repair from LPLCs.
      • Boulter L.
      • Govaere O.
      • Bird T.G.
      • Radulescu S.
      • Ramachandran P.
      • Pellicoro A.
      • Ridgway R.A.
      • Seo S.S.
      • Spee B.
      • Van Rooijen N.
      • Sansom O.J.
      • Iredale J.P.
      • Lowell S.
      • Roskams T.
      • Forbes S.J.
      Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease.
      ,
      • Reddy S.M.
      • Hsiao K.H.K.
      • Abernethy V.E.
      • Fan H.
      • Longacre A.
      • Lieberthal W.
      • Rauch J.
      • Koh J.S.
      • Levine J.S.
      Phagocytosis of apoptotic cells by macrophages induces novel signaling events leading to cytokine-independent survival and inhibition of proliferation: activation of Akt and inhibition of extracellular signal-regulated kinases 1 and 2.
      In detail, the depletion of Kupffer cells did not influence the proliferation of LPLCs but reduced their invasive behavior.
      • Van Hul N.
      • Lanthier N.
      • Español Suñer R.
      • Abarca Quinones J.
      • van Rooijen N.
      • Leclercq I.
      Kupffer cells influence parenchymal invasion and phenotypic orientation, but not the proliferation, of liver progenitor cells in a murine model of liver injury.
      The direct cell-cell communication between LPLCs and myofibroblasts has been shown to involve the interactions of lymphotoxin β,
      • Ruddell R.G.
      • Knight B.
      • Tirnitz-Parker J.E.E.
      • Akhurst B.
      • Summerville L.
      • Subramaniam V.N.
      • Olynyk J.K.
      • Ramm G.A.
      Lymphotoxin-β receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury.
      as well as the role of extracellular matrix deposition in LPLC expansion and differentiation.
      • Pintilie D.G.
      • Shupe T.D.
      • Oh S.
      • Salganik S.V.
      • Darwiche H.
      • Petersen B.E.
      Hepatic stellate cells’ involvement in progenitor-mediated liver regeneration.
      The reduction in LPLC parenchymal invasion by the depletion of Kupffer cells has been proved to be attributed to the reduced activation of myofibroblasts and the decrease in the extracellular matrix framework, which is necessary for cell motility.
      • Van Hul N.
      • Lanthier N.
      • Español Suñer R.
      • Abarca Quinones J.
      • van Rooijen N.
      • Leclercq I.
      Kupffer cells influence parenchymal invasion and phenotypic orientation, but not the proliferation, of liver progenitor cells in a murine model of liver injury.
      It has been well-described that the polarization of macrophages plays an important role in liver injury and liver regeneration, with a pro-inflammatory M1 polarization and an alternative anti-inflammatory M2 polarization.
      • Sica A.
      • Invernizzi P.
      • Mantovani A.
      Macrophage plasticity and polarization in liver homeostasis and pathology.
      ,
      • Besnard A.
      • Julien B.
      • Gonzales E.
      • Tordjmann T.
      Innate immunity, purinergic system, and liver regeneration: a trip in complexity.
      Similar to the opposite polarization types of macrophages, infiltrating monocytes can also be separated into 2 subtypes characterized by different Ly-6C (Gr-1) expression levels in mice, Ly-6Chigh monocytes, which are considered to promote tissue injury, and Ly-6Clow monocytes, which can suppress inflammation and facilitate liver repair.
      • Tacke F.
      • Zimmermann H.W.
      Macrophage heterogeneity in liver injury and fibrosis.
      • Vannella K.M.
      • Wynn T.A.
      Mechanisms of organ injury and repair by macrophages.
      • Tacke F.
      • Randolph G.J.
      Migratory fate and differentiation of blood monocyte subsets.
      In an ALD mouse model, Ly6Chigh monocytes were found to develop progressively into Ly6Clow monocytes upon phagocytosis of apoptotic hepatocytes in mild liver injury. However, in cases of severe injury, the phenotype switching from Ly6Chigh to Ly6Clow monocytes might be blocked, thereby resulting in persistent hepatic inflammation and impaired liver injury.
      • Wang M.
      • You Q.
      • Lor K.
      • Chen F.
      • Gao B.
      • Ju C.
      Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice.
      Also, macrophage polarization has a key role in the progression of nonalcoholic fatty liver disease, driving LPLC response by Wnt3a production.
      • Carpino G.
      • Nobili V.
      • Renzi A.
      • De Stefanis C.
      • Stronati L.
      • Franchitto A.
      • Alisi A.
      • Onori P.
      • De Vito R.
      • Alpini G.
      • Gaudio E.
      Macrophage activation in pediatric nonalcoholic fatty liver disease (NAFLD) correlates with hepatic progenitor cell response via Wnt3a Pathway.
      Kupffer cells also turned out to control the initial accumulation of monocyte-derived macrophages, which in turn are responsible for LPLCs proliferation.
      • Elsegood C.L.
      • Chan C.W.
      • Degli-Esposti M.A.
      • Wikstrom M.E.
      • Domenichini A.
      • Lazarus K.
      • van Rooijen N.
      • Ganss R.
      • Olynyk J.K.
      • Yeoh G.C.T.
      Kupffer cell-monocyte communication is essential for initiating murine liver progenitor cell-mediated liver regeneration: liver injury/regeneration.
      Furthermore, Viebahn et al
      • Viebahn C.S.
      • Benseler V.
      • Holz L.E.
      • Elsegood C.L.
      • Vo M.
      • Bertolino P.
      • Ganss R.
      • Yeoh G.C.T.
      Invading macrophages play a major role in the liver progenitor cell response to chronic liver injury.
      identified potential synergy between LPLCs and macrophages through ligand-receptor interaction, which is based on the recruitment of macrophages to the damaged liver by LPLCs.

      Natural Killer Cells in Liver Progenitor-Like Cell–Induced Liver Regeneration

      Another important innate immune cell subset in liver regeneration is NK cell, which constitutes 30%–50% of the intrahepatic lymphocytes in humans, playing a vital role in suppressing hepatic bacterial and viral infections.
      • Sun H.
      • Sun C.
      • Tian Z.
      • Xiao W.
      NK cells in immunotolerant organs.
      Although it has been proved that the activation of NK cells inhibited liver regeneration via the production of interferon (IFN)-γ after PHx,
      • Sun R.
      • Gao B.
      Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-γ).
      the role of NK cells in chronic liver injury was controversial. The activated NK cells in a CCl4 mouse model turned out to inhibit the liver regeneration via the production of tumor necrosis factor α,
      • Wei H.
      • Wei H.
      • Wang H.
      • Tian Z.
      • Sun R.
      Activation of natural killer cells inhibits liver regeneration in toxin-induced liver injury model in mice via a tumor necrosis factor-α-dependent mechanism.
      which also played a beneficial role in LPLCs proliferation to replace dying hepatocytes.
      • Cosgrove B.D.
      • Cheng C.
      • Pritchard J.R.
      • Stolz D.B.
      • Lauffenburger D.A.
      • Griffith L.G.
      An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-α.
      Also, CXCL7 secreted by NK cells could induce the recruitment of mesenchymal stem cells, thereby improving liver regeneration.
      • Almeida C.R.
      • Caires H.R.
      • Vasconcelos D.P.
      • Barbosa M.A.
      NAP-2 secreted by human NK cells can stimulate mesenchymal stem/stromal cell recruitment.
      In addition, conventional NK cells have been proved to predominantly produce interleukin (IL) 22, which could promote the regeneration of epithelial cells and the production of antimicrobial peptides, effectively preventing secondary opportunistic infections during influenza infection.
      • Kumar P.
      • Thakar M.S.
      • Ouyang W.
      • Malarkannan S.
      IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection.
      Therefore, NK cells can produce cytokines that are important for liver regeneration.
      Considering the negative effect of overactivated NK cells on liver regeneration, researchers have focused on controlling NK cells activation by inhibitory receptors.
      • Long E.O.
      • Sik Kim H.
      • Liu D.
      • Peterson M.E.
      • Rajagopalan S.
      Controlling natural killer cell responses: integration of signals for activation and inhibition.
      • Ndhlovu L.C.
      • Lopez-Vergès S.
      • Barbour J.D.
      • Jones R.B.
      • Jha A.R.
      • Long B.R.
      • Schoeffler E.C.
      • Fujita T.
      • Nixon D.F.
      • Lanier L.L.
      Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity.
      • Yu X.
      • Harden K.
      • C Gonzalez L.
      • Francesco M.
      • Chiang E.
      • Irving B.
      • Tom I.
      • Ivelja S.
      • Refino C.J.
      • Clark H.
      • Eaton D.
      • Grogan J.L.
      The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells.
      • Bi J.
      • Zheng X.
      • Chen Y.
      • Wei H.
      • Sun R.
      • Tian Z.
      TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk.
      The coinhibitory receptor TIGIT turned out to mediate the self-tolerance of NK cells regenerative hyperplasia by interacting with poliovirus receptor expressed on Kupffer cells, thereby limiting innate immunity against the liver regeneration.
      • Bi J.
      • Zheng X.
      • Chen Y.
      • Wei H.
      • Sun R.
      • Tian Z.
      TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk.
      Thus, the negative effects induced by the overactivation of NK cells can be potentially reduced by various inhibitory receptors. Considering the possible negative effects of LPLC-induced liver regeneration during chronic liver disease, such as liver fibrosis and hepatocarcinoma, NK cells have also been researched in such diseases. Recently, Saparbay et al
      • Saparbay J.
      • Tanaka Y.
      • Tanimine N.
      • Ohira M.
      • Ohdan H.
      Everolimus enhances TRAIL-mediated anti-tumor activity of liver resident natural killer cells in mice.
      have demonstrated that the treatment of Everolimus could enhance the antitumor activity of immature liver-resident NK cells through the up-regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), consistent with an earlier study showing that liver-resident NK cells were distinctly characterized by expression of TRAIL,
      • Ochi M.
      • Ohdan H.
      • Mitsuta H.
      • Onoe T.
      • Tokita D.
      • Hara H.
      • Ishiyama K.
      • Zhou W.
      • Tanaka Y.
      • Asahara T.
      Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice.
      which could attack virus-infected and tumor cells.
      • Almasan A.
      • Ashkenazi A.
      Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy.
      For liver fibrosis, NK cells could kill activated HSCs via RAE1/NKG2D- and TRAIL-dependent mechanisms, thereby controlling and ameliorating liver fibrosis,
      • Radaeva S.
      • Sun R.
      • Jaruga B.
      • Nguyen V.T.
      • Tian Z.
      • Gao B.
      Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor–related apoptosis-inducing ligand–dependent manners.
      indicating the important role of NK cells in suppressing liver fibrosis during hepatitis B virus or hepatitis C virus. Furthermore, TWEAK has been proved to play a key role in regulating goat peripheral NK cell cytotoxicity and cytokine expression levels during the progression of PPRV.
      • Qi X.
      • Li Z.
      • Li H.
      • Wang T.
      • Zhang Y.
      • Wang J.
      MicroRNA-1 negatively regulates peripheral NK cell function via tumor necrosis factor-like weak inducer of apoptosis (TWEAK) signaling pathways during PPRV infection.
      Because TWEAK signaling contributes to the initiation of LPLCs activation, it may have dual function in LPLC-induced liver regeneration.
      Accounting for 10%–15% of human liver lymphocytes, NKT cells, a population of cells expressing NK and T-cell markers,
      • Exley M.A.
      • Koziel M.J.
      To be or not to be NKT: natural killer T cells in the liver.
      ,
      • Bendelac A.
      • Savage P.B.
      • Teyton L.
      The biology of NKT cells.
      have also been studied in liver injury and liver regeneration. Similar to macrophages, NKT cells can also be categorized into pro-inflammatory type I NKT cells and anti-inflammatory type II NKT cells.
      • Kumar V.
      NKT-cell subsets: promoters and protectors in inflammatory liver disease.
      Type I NKT cells, also called classical or invariant NKT cells, comprise 95% of liver NKT cells and express a semi-invariant T-cell receptor, whereas type II NKT cells comprise less than 5% of liver NKT cells and express more diverse T-cell receptors.
      • Brennan P.J.
      • Brigl M.
      • Brenner M.B.
      Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions.
      Because most of the liver NKT cells have been proved to be invariant NKT, they were initially believed to play a negative role in liver regeneration by releasing cytokines such as IFN-γ and IL4 or direct cytotoxicity. In hepatitis B virus transgenic mice, Dong et al
      • Dong Z.
      • Zhang J.
      • Sun R.
      • Wei H.
      • Tian Z.
      Impairment of liver regeneration correlates with activated hepatic NKT cells in HBV transgenic mice.
      found that the impairment of liver regeneration was not only due to IFN-γ overproduction by activated hepatic NKT cells but might also be relevant to hepatocyte itself, which was more sensitive to exogenous stimulus. For direct hepatotoxicity, NKT cells could kill hepatocytes by releasing FasL.
      • Takeda K.
      • Hayakawa Y.
      • Van Kaer L.
      • Matsuda H.
      • Yagita H.
      • Okumura K.
      Critical contribution of liver natural killer T cells to a murine model of hepatitis.
      However, in chronic liver injury, which will lead to liver fibrosis associated with the accumulation of collagen in the liver,
      • Friedman S.L.
      Mechanisms of hepatic fibrogenesis.
      the impact of NKT cells on LPLC-induced liver regeneration seemed to be controversial. Similar to NK cells, NKT cells can inhibit HSC activation by killing activated HSCs, thus inhibiting liver fibrosis. However, the protective effect was only discovered in the earlier stages and not in the later stages of liver fibrosis.
      • Park O.
      • Jeong W.I.
      • Wang L.
      • Wang H.
      • Lian Z.X.
      • Gershwin M.E.
      • Gao B.
      Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride.
      Also, IL22 produced by NK and NKT cells has been finely demonstrated to improve liver regeneration by increasing HSCs senescence via STAT3 activation, as well as promoting LPLCs.
      • Khawar M.B.
      • Azam F.
      • Sheikh N.
      • Abdul Mujeeb K.
      How does interleukin-22 mediate liver regeneration and prevent injury and fibrosis?.
      In addition, the chemokine receptor CXCR6, which is predominantly expressed on NKT cells, could protect liver from inflammation and fibrosis in NEMOLPC-KO mice, in which increased hepatocyte apoptosis and compensatory regeneration caused steatosis, inflammation, and fibrosis.
      • Liepelt A.
      • Wehr A.
      • Kohlhepp M.
      • Mossanen J.C.
      • Kreggenwinkel K.
      • Denecke B.
      • Costa I.G.
      • Luedde T.
      • Trautwein C.
      • Tacke F.
      CXCR6 protects from inflammation and fibrosis in NEMOLPC-KO mice.
      In NKT cell-deficient mice, the impairment of Cyclin B1 and p21 expression could induce reduced liver regeneration.
      • Ben Ya’acov A.
      • Meir H.
      • Zolotaryova L.
      • Ilan Y.
      • Shteyer E.
      Impaired liver regeneration is associated with reduced cyclin B1 in natural killer T cell-deficient mice.
      Thus, NKT cells are necessary and even beneficial for LPLCs-induced liver regeneration during chronic liver injury.

      Therapies Improve Liver Regeneration Based on Innate Immune Cells for Chronic Liver Disease

      With a diversity of complications and the result of liver fibrosis and hepatocarcinoma, the treatment to chronic liver diseases associated with LPLC-induced liver regeneration is an urgent but challenging problem. So far, most of the studies have been carried out on cell therapies based on macrophages. For example, bone marrow cell therapy has shown promising protective results in liver regeneration.
      • Bird T.G.
      • Lu W.Y.
      • Boulter L.
      • Gordon-Keylock S.
      • Ridgway R.A.
      • Williams M.J.
      • Taube J.
      • Thomas J.A.
      • Wojtacha D.
      • Gambardella A.
      • Sansom O.J.
      • Iredale J.P.
      • Forbes S.J.
      Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling.
      ,
      • Thomas J.A.
      • Pope C.
      • Wojtacha D.
      • Robson A.J.
      • Gordon-Walker T.T.
      • Hartland S.
      • Ramachandran P.
      • Van Deemter M.
      • Hume D.A.
      • Iredale J.P.
      • Forbes S.J.
      Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function.
      • Tacke F.
      Targeting hepatic macrophages to treat liver diseases.
      • Starkey Lewis P.J.
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      It has been proved that the M1 polarized BMDMs exhibited better therapeutic effects than non-polarized M0 BMDMs, which was attributed to their ability to attenuate liver fibrosis and improve liver regeneration by recruiting monocyte-derived macrophages and NK cells, thus promoting collagen degradation, HSC apoptosis, and LPLC proliferation.
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      Therefore, the different polarization phenotypes of macrophages played a crucial role in liver regeneration and provided various methods for the treatment of chronic liver diseases.
      Macrophages and NK cells are 2 subsets indispensable for liver regeneration. Therefore, scientists have researched the interplay between them in the hope of better outcomes for chronic liver diseases. Ma et al
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      identifying PTEN as a potential target for liver regeneration. For NK cells, they have been previously proved to be beneficial for attenuating inflammation and preventing adverse cardiac remodeling via the cell crosstalk with allogeneic human cardiac-derived progenitor cells,
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      Natural killer cell crosstalk with allogeneic human cardiac-derived stem/progenitor cells controls persistence.
      implying their potential roles in LPLC-induced liver regeneration. In a Fah−/− liver failure mouse model, the activated NK cells showed a vital role in bone marrow-derived hepatocyte generation, facilitating the fusion of myelomonocyte and hepatocyte in an IFN-γ–dependent manner.
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      In addition, NK cells also showed direct roles in preventing liver fibrosis in a thioacetamide-induced liver fibrosis mouse model through its activation by Fasudil, a Ras homology family member A kinase inhibitor.
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      NKT cell subsets as key participants in liver physiology and pathology.
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      Selective elimination of hepatic natural killer T cells with concanavalin A improves liver regeneration in mice.
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      • Hammerich L.
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      • Pack O.
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      • Trautwein C.
      • Tacke F.
      Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis.
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      • Sun R.
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      • Lian Z.
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      • Tian Z.
      Oral ampicillin inhibits liver regeneration by breaking hepatic innate immune tolerance normally maintained by gut commensal bacteria.
      which could explain why the overuse of antibiotics induced impaired liver function and liver regeneration. With the in-depth understanding of NKT cells, Martin-Murphy et al
      • Martin-Murphy B.V.
      • Kominsky D.J.
      • Orlicky D.J.
      • Donohue T.M.
      • Ju C.
      Increased susceptibility of natural killer T-cell-deficient mice to acetaminophen-induced liver injury.
      proved that NKT cells could protect mice from acetaminophen-induced liver injury probably by producing IL4. It remains unknown whether NKT cells can be developed to promote liver regeneration by taking advantage of 2 subpopulations with opposite effects like macrophages. Thus, further exploration is needed to investigate the therapeutic roles of NK cells and NKT cells in liver regeneration during chronic liver injury.

      Conclusions

      In summary, macrophages can not only promote the proliferation of LPLCs through TWEAK signaling but also induce the differentiation of LPLCs into hepatocytes via Wnt3a pathway. The macrophage-based cytotherapy has been proved to be beneficial for liver regeneration. In addition, treatments polarizing macrophages to a more restorative phenotype can also help repair the liver. For NK cells, they play a beneficial role in viral hepatitis because of their ability to suppress liver fibrosis, which is the major negative effect of LPLC-induced liver regeneration. However, the overaction of NK cells may lead to the overproduction of IFN-γ, thus leading to impaired liver regeneration. Thus, treatments based on NK cells mainly focus on the control of NK cells activation to take advantage of their beneficial roles. NKT cells, another subset of innate immune cells, can also be categorized into pro-inflammatory type I and restorative type II NKT cells, but they have been less researched in liver regeneration compared with macrophages and NK cells. Considering the important role of LPLCs in liver regeneration during chronic liver injury, further studies based on these 3 kinds of innate immune cells are required because of their close relationship with LPLCs.

      CRediT Authorship Contributions

      Yihan Qian (Resources: Lead; Visualization: Lead; Writing – original draft: Lead)
      Zhi Shang (Funding acquisition: Equal; Resources: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal)
      Yueqiu Gao (Supervision: Supporting; Writing – review & editing: Supporting)
      Hailong Wu (Project administration: Lead; Supervision: Lead; Writing – review & editing: Equal)
      Xiaoni Kong, PhD (Funding acquisition: Lead; Project administration: Lead; Supervision: Lead; Writing – review & editing: Lead)

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