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Liver regeneration- principles, measurement and status
Perceptor Prof. S K Acharya
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Introduction• Liver possesses an
ability to regenerate following partial resection until it attains its original size
• Clinically important- this can be an alternative to liver transplantation
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Introduction• Regeneration means the reconstitution of a
structure that has been excised. Eg. complete re-growth of the limb of a newt or tail of lizard
• In c/o liver it is actually compensatory hyperplasia rather than true regeneration
• Total liver mass rather than the lobulated anatomic configuration is restored
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Introduction• In normal liver fewer than 1 in 10,000 hepatocytes
undergo mitosis at any given time, they remain in Go
• Normal hepatocytes respond poorly to mitogens like TGF, EGF & HGF
• Liver possesses a unique capacity to replace tissue mass after injury or loss of liver mass
• Regenerative capacity is insufficient - CVH or alcoholism- cirrhosis
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Experimental models
• Model to study liver regeneration is removal of 2/3 of the liver of rats/mice a technique known as 2/3 PHx • Liver cells proliferate - original liver mass is restored within 5-7 days• No massive inflammation, fibrosis or scarring
Bucher NL. Regeneration of Mammalian Liver.Int. Rev. Cytol.1963;15: 245–300
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The regenerating liver
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Rodent model
• Hepatocytes are the first to enter the cell cycle• Undergo 2 rounds of cell division within 2–3
days• Proliferation of hepatic stellate cells, Kupffer
cells and biliary epithelial cells• Angiogenesis (endothelial cells) occur to re-
establish the liver vasculature
Bucher NL. Regeneration of Mammalian Liver.Int. Rev. Cytol.1963;15: 245–300
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Rodent model
• The advent of gene knock out mice - various specific molecules and dissection of pathways
• No single GM mouse model demonstrates 100% mortality and a complete blockage of both DNA replication and cell proliferation
• No single gene can be considered “essential” for liver regeneration
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Severity of liver injury and regeneration
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Networks during liver regeneration
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Check points in cell division• Hepatocytes in the
normal liver are quiescent (Go phase) and respond minimally to in vivo mitogens such as TGF EGF and HGF
• These mitogens can induce replication following infusion of TNF-a
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Timing of Regeneration
• In rat, DNA synthesis peaks at 24 hours after PH, when approximately 35% of hepatocytes are in cell cycle
• Observed- circadian clock controls the G2/M transition
• G2-M transition always occur at the same time of day
Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H. Control mechanism of the circadian clock for timing of cell division in vivo. Science 2003;302:255-25
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Timing of Regeneration
• Mammals- Circadian timing system controlled by pacemaker in the suprachiasmatic nucleus of the brain
• Synchronizes subsidiary circadian oscillators in peripheral cell types including hepatocytes
Matsuo T. Control mechanism of the circadian clock for timing of cell division in vivo. Science 2003;302:255-25
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Timing of Regeneration
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Genes and cyclins in regeneration
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Immediate Early Genes
• Activated almost immediately (within minutes) after partial hepatectomy in mice
• 70 immediate early genes and more– Proto-oncogenes c-fos, c-jun, c-myc, and c-ets– Transcription factors- NFκB , STAT3, IGF
binding protein-1 etc
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NFΚB AND IMMEDIATE EARLY GENES
• Quiescent liver NFκB in the cytosol bound to IkB
• Binding of TNF-a to TNF-R1- IkB kinase- Phosphrln of IκB
• Free NFkB Translocates to nucleus
• Transcription of IL-6• Activation of STAT3
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Delayed Early Genes
• Transcribed after the immediate early gene response – Expression occurs during later phases – Depends on protein synthesis; Tr Factors– HRS/SRp40 (splicing factor and modulator of alternative
splicing of RNA transcripts) and the anti apoptotic gene bcl-x
• Pro-apoptotic genes BAK, BAD, BAX - down-regulated
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Cyclins and CDKs• Family of proteins that
control the progression of cells through the cell cycle by activating Cdk
• CDk- ser/threo kinases inactive
• Cyclin attachment activation• All CDKs perform
phosphorylation of target proteins
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Cyclin concentration wrt cell cycle
Cyclin_Expression.svg
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Cyclins and CDKs• G1 phase; CDKs catalyze the phosphorylation of
the pRb and cause its dissociation from the E2F family of proteins
• This eliminates the repression of gene expression by pRB
• Cyclin D1 also may sequester the cell cycle inhibitor p27 with advancement in cell cycle
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Integration of Cytokines and Growth Factors in Liver Regeneration
• Priming– 0-5 hrs– Reversible phase in liver regeneration, G0 - G1
phase– Cytokines, eg. TNF-α and IL-6– NFκB and STAT3 are activated– Sensitize hepatocytes to growth factors
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Integration of Cytokines and Growth Factors in Liver Regeneration
• Progression– Requires HGF (mesenchymal cells) and TGF-α (hepatocyte) &
cyclins– During the progression phase, the cells move past the
restriction point in G1 to S and beyond– GH, PTH, T3 are permissive for liver regeneration – Insulin and norepinephrine are adjuvant factors
• HGF and c-met – Sources of HGF in the liver are Kupffer cells and HSC– HGF binding to of c-met activates tyrosine kinase and thus
initiates a signal transduction pathway
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Summary; the sequence of signals that leads to liver regeneration
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Mitogenic Signals Associated With Initiation of Liver Regeneration
• Quiescent hepatocytes express a variety of GF receptors; PDGF, VEGF, FGF receptors
• Only mitogens for hepatocytes in media are HGF and ligands of the EGFR ; EGF, TGFα, AR, HBEGF, etc
• Direct mitogens- induce a strong mitogenic response in hepatocytes
• HGF, EGF, and TGFα also induce hepatocyte proliferation when injected into mice and rats
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Mechanisms of regeneration in ALF• STAT3 translocates to the nucleus with induction
of transcription of target genes • Go- G1; driven by HGF and EGF receptor ligand
family • Serum levels of HGF have been found to be
markedly elevated in the serum of adults and children in ALF
Changes in serum levels of hepatocyte growth factor in patients undergoing adult-to-adult living-donor liver transplantation. Transplantation 2003;76:1769–1770
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Oval cells • HPCs- generated from the biliary compartment
in response to hepatic injury • Canals of herring, or in periductular situation• Capable of generating cholangiocytes or
hepatocytes • Growth factors that stimulate oval cell
proliferation are similar to those that stimulate hepatocyte replication
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Oval cells
• Murine liver +ve for – Immature markers - α-fetoprotein– Mature hepatic markers (e.g., albumin) – Biliary markers (e.g., cytokeratin-19)
• c-kit, CD34, Ov6, CK7, cgnn A + • Oval cells and hepatocytes require signaling
through TNF-R1; but not simultaneously • TGF beta - oval cell replication is less affected
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Oval cells• HPCs proliferate in the
portal zone • “Streaming liver hypothesis”
– migrate toward the central vein in the liver lobules as daughter hepatocytes
• Proven with Mt DNA mutation tracking - in the human liver as well as in regenerative nodules in cirrhosis
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Bone Marrow Stem Cells inLiver Disease
• Stem cells - totipotent, pluripotent, multipotent, or unipotent
• 2 endogenous populations of stem cells in liver- Hepatocytes and hepatic oval cells
• Hepatocytes ; able to self-renew limitlessly often play the principal role in liver regeneration
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Hematopoetic stem cells
• Liver - location of hematopoiesis in fetus• ?Hematopoetic stem cells remain behind to
form HSC– HSCs can share cell surface markers associated
with hematopoietic stem cells such as CD34, Thy-1 and c-kit
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Can Hematopoietic Cells Generate Hepatocytes?
• Data from Murine Models– BM-HSC have been
demonstrated to repopulate liver and give rise to functional hepatocytes
– BM HSC derived hepatocytes- arise from cell fusion of donor HSC and recipient hepatocytes
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Can Hematopoietic Cells Generate Hepatocytes?
• Allogeneic bone marrow cells transplanted into lethally irradiated mice- generate hepatocyte-like cells in the liver at very low frequency (1/ 10,000)
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Clinical Data from Sex-Mismatched BM Transplants
• Microchimerism; Presence of cells that originate from another individual and are genetically distinct from the cells of the host individual
• Frequency of BMHSC derived hepatocytes varied between <1% and 8% in sex mismatched individuals– Higher frequencies in pediatric liver allografts– Microsatellite analyses- higher percentage of
chimerism in comparison to Y chromosome evaluation by FISH
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Liver regeneration in acute severe liverimpairment: a clinicopathologicalcorrelation study• N = Liver Bx samples of 74 patients with ALF/SALF• Etiology; acute HAV + drug toxicity (n 3), acute HBV (n
10), drug induced (n 21) and cryptogenic (n 40) • Mean age: 43+17 years• M/F: 28/ 46
– IHC for CK7/CK19 – HPCs activation/differentiation – Ki 67/P21 - proliferative activity/proliferation arrest – H & E - hepatocyte loss
Aezam Katoonizadeh. Liver international 2006
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Liver regeneration in acute severe liverimpairment
Group Aalive (n 24)
Group Bdied (n 10)
Group Ctransplanted (n 40)
P value
>50% hepatocyte loss
8% (2/24) 80% (8/10) 95% (38/40) <0.0001
proliferating hepatocytes
14.3+9.3 2.5 +2.5 5.7+7.3 <0.0001
Number of HPC 74+55 138+52 141+58 <0.003
Intermediate hepatocytes
63% (15/24) 50% (5/10) 83% (33/40) NS
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Liver regeneration in acute severe liver impairment
• Oval cell activation requires 50% loss of hepatocytes, a/w significant decrease in the proliferative activity of remaining hepatocytes
• Associated with poor prognosis
Aezam Katoonizadeh. Liver international 2006
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Mesenchymal Stem Cells as a Source forLiver Regeneration
• Multipotent stromal cells that can differentiate into osteoblasts, chondrocytes , adipocytes
• In vitro; Differentiate into hepatocyte like cells and hepatic epithelial cells
• Umbilical cord blood, wharton’s gelly, adipose tissue–Hypoimmunogenic and create immuno
suppressive microenvironment–1 gram of fat > no of stem cells 1 gram of
marrow
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Mesenchymal Stem Cells as a Source forLiver Regeneration
• In vitro functional assays- hepatocyte characteristics – albumin production– glycogen storage– urea secretion–uptake of LDL
• Studies in humans hindered by–Safety concerns–Lack of molecular data – Immunological mismatch
Gut,vol.58,no.4
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Hepatocyte transplantation
• Involves the transfer of normal hepatocytes into diseased liver
• Isolated hepatocytes injected into splenic artery or directly into the portal vein
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Hepatocyte transplantation
• Host liver architecture remains intact following the integration of hepatocytes in liver cords
• Transplantation is metabolically less stressful than whole liver transplants
• Consequences of graft loss are much less severe• Does not interfere with subsequent liver
transplantation or gene therapy
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Murine studies in Hepatocyte transplantation
• Murine model- u TPA over producing cells– 10 4 liver cells – replace more than 80% of the liver– donor hepatocytes capable of at least 12 rounds
of cell division
Replacement of diseased mouse liver by hepatic cell transplantation. Science.263:1149–1152
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Murine studies in Hepatocyte transplantation
• Intraperitoneal injections of hepatocytes into rats with fulminant hepatic failure induced by D galactosamine– improved survival – donor liver cells did not repopulate the liver
Cellular transplantation in the treatment of experimental hepatic failure. Science. 1980. 210:901–903
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Methods for Assessing Liver Regeneration
• Need to accurately document the extent of hepatic regenerative activity –Patients with liver disease –Partial hepatic resections –Receiving interventions designed to
stimulate hepatic regeneration
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Methods for Assessing Liver Regeneration
• Ideally–Non invasive, in-vivo–Measuring only specific phase
of cell cycle–Sensitive and Specific
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Methods for Assessing Liver Regeneration
• Tissue determination– Liver weight
– CT/MRI- estimated weight (in grams) equals 0.81 × hepatic volume in ml +372
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Mitosis measurement
• Incubating hepatocytes with potassium chloride and alcohol
–Centrifugation– McNeill's stain–No of mitotic figures per 1000 cells per
hpf–No of mitotic figures available for
counting is relatively limited
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DNA synthesis
• Thymidine labelling index – TK rate limiting enzyme for DNA synthesis– Phosphorylates thymidine ; subsequent
incorporation into the DNA– Liver biopsy tissues or isolated hepatocytes
are incubated with radiolabelled thymidine for 1 h prior to measuring radioactivity
– Standardized and reproducible marker of hepatic regenerative activity
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DNA synthesis
• Bromodeoxyuridine incorporation – BdU- thymidine analogue , incorporated into
DNA during DNA synthesis– Incorporation detected by IHC– Labeling index per 1000 hepatocytes/HPF• 1% in resting livers• 25-36% in hepatocytes and sinusoidal cells derived
from livers 24 h and 48 h following partial hepatectomy
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Immunohistochemistry
– PCNA – Ki-67 – DNA polymerase alpha – NOR proteins
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KI 67 Labelling index
• KI-67 is a nuclear protein that is needed for cellular proliferation
• Inactivation - inhibition of ribosomal RNA synthesis
• Appears in early G1, peaks during S & M• Cellular marker for proliferation• Fraction of Ki-67-positive cells is correlated
with replication of cells
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Proliferating Cell Nuclear Antigen
• Processivity factor for DNA polymerase delta• Processivity is the ability to catalyze
consecutive reactions without releasing substrate
• S phase of cell cycle• Antibodies against PCNA is used as a marker of
cell replication
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DNA polymerase alpha
• Appears in the cell nucleus during the G1 phase & present during the S and G2 phases
• Monoclonal anti-DNA alpha antibodies have been developed
• Relatively simple to perform
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NOR proteins• Nucleolar Organizer Region (NOR) associated
proteins - collection of acidic proteins with nucleolin and B-23 as components
• 3 fold increase in NOR protein levels - after partial hepatectomy in rats
• NOR proteins may be used as a marker of hepatocyte proliferation
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Endogenous gene expression
• H3 histone mRNA • Transcription rates increase 10-fold at the
onset of S phase
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Enzyme and protein levels in liver tissue
Thymidine kinase level Results correlate well with PCNA and
thymidine incorporation Ornithine decarboxylase and hepatic
putrescine ODC- Enzyme expressed by regenerating liver cells Synthesise polyamine putrescine
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Conclusion• The pursuit of understanding liver
regeneration has yielded great progress in last few decades
• However, many aspects of this phenomenon remain to be further understood
• On learning the regulatory networks- options may open up for therapy in ALF , small for size Txn, extensive resection and Rx of cirrhosis among many other conditions
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Thank you