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Liver regeneration from stem cells

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Liver regeneration from stem cells

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Dr. PéterBalogh and Dr. Péter Engelmann Transdifferentiation and regenerative medicine – Lecture 8 Liverregenerationfromstemcells

  3. Structure of thehepaticlobe Bilecanaliculi Centralvein Centralvein Portaltracts (triads) Sinusoids Bileduct Portaltract Branchportal vein Branchhepatic artery Periportal (6-8 cells) Centrilobular (8-10 cells) Glutaminesynthetase + (1-3 cells) Limiting plate

  4. Clinical necessity of liver regeneration • Shortage of livers for orthotopic liver transplantation • Liver cell transplantation – limited amount • Choice of stem cell candidates – variable success in experimental conditions

  5. Main phases of liverregeneration 1 Migration 3 Clearance Physical/chemical/geneticalstimulus Gadoliniumchloride/ monocrotaline Organdamage Deadcell MMP-9 Centralvein Kupffercells (phagocytosis) Centralvein SDF-1 HGF (SCF) Recruitment Stemcells (c-kit, c-met, CXCR4) Immunosuppression Encapsulation Co-transplantation Effectorcells Monocrotaline Doxorubicin Hepaticinjury VEGF 2 Integration VEGF HGF TGF FGF Centralvein Organdamage Alteration of blood flow Vasodilatators Sinus endothel permeability Gapjunctions Variablein vivo cellphenotype MMP-9 MMP-2 MT1-MMP Cellloss of 70-80%

  6. Developmentalrelationshipbetweenhepatic-pancreaticdifferentiationDevelopmentalrelationshipbetweenhepatic-pancreaticdifferentiation ? Ovalcellprogenitor Pancreatic progenitor(s) Hepatic oval cell Pancreatic oval cell Bile duct Hepatocyte Endocrine cell Pancreatic duct Acinar cell

  7. Transcriptional control of hepatoblast development Hepatoblast HGF C/EBP HNF-6 Tbx3 HNF-1 Wnt BMP+FGF FoxM1B ECM HNF-4 Notch2 Cholangiocyte Hepatocyte Albumin ? ECM C/EBP Hex Jagged Core transcription factor network: HNF-6/OC-2 TGF HNF-4 HNF-1 HNF-6 Parenchyma Periportal HNF-1 LRH-1 Foxa2 Sox9 HNF-1 Hepatocyte maturation cords Cholangiocyte maturation ducts

  8. Oval cells – adult liver stem/progenitor cells • Origin: debated (their precursors are associated with the biliary tree) • Bipotential differentiation: hepatocyte and cholangiocyte • Phenotype: shared markers with adult hepatocytes (albumin, cytokeratins 8 and 18), bile duct cells (cytokeratins 7 and 19, OV-6, A6), fetal hepatoblasts (AFP), and haematopoietic stem cells (Thy -1, Sca-1, c-kit).

  9. Cellular targets for hepatic regeneration • Hepatocytes: metabolic activity of the liver • Cholangiocytes: formation of bile ducts • Both derive from embryonic endodermal epithelium.

  10. Stages and forms of liver regeneration • Surgical partial hepatectomy – from hepatocytes (often polyploid cells) • Possible sources: hepatocytes, oval cells and extrahepatic stem cells (HSC?) • Assessment of lineage commitment: albumin, glucose-6-phosphatase, transferrin and transthyretin (hepatic). • Fibrotic regeneration: transformation of fibrocytes into myofibroblasts • Parenchymal regeneration: regeneration of hepatocytes

  11. Sequence of parenchymal regeneration of the liver • Stem cell migration into the liver parenchyma is directed by chemoattractive agents (as SDF-1, HGF and SCF) secreted by damaged liver cells • Increased MMP-9 expression by host hepatocytes after injury, leading to ECM remodeling and increased vascular permeability • Transformation of local microenvironment for the integration and proliferation of the transplanted cells, including local secretion of cytokines/growth factors (HGF, FGF, TGFa). Dead cells will be phagocyted by Kupffer cells.

  12. Oval cell activation and expansion • Liver injury activates oval cells (their precursors in the biliary tree?) AND other support cells (stellate cells, macrophages/Kupffer’s cells, NK cells, endothelium, etc) • Homing/intrahepatic migration to the site of injury • Proliferation and bidirectional differentiation (hepatocyte/cholangiocyte)

  13. Non-hepatic cells for liver regeneration • Autologous: Bone marrow-derived/mesenchymal stem cells – fibroblastic regeneration • Allogenic: Fetal-derived hepatocytes or embryonic stem cell-derived liver cells

  14. Differentiation of iPS cells into hepatocytes • Induction of iPS cells: transfection with TFs • Formation of embryoid bodies • Induction of endodermal commitment: treatment with Activin A and bFGF • Differentiation into hepatocytes: treatment with hepatocyte growth factor (HGF) • Assessment: gene expression, albumin secretion, glycogen storage, urea production, and inducible cytochrome activity

  15. Summary • Depending on the origin/type of liver damage, different regeneration processes operate, thus (a) in loss of liver mass, the regeneration is initiated from hepatocytes, whereas (b) in toxicity from hepato-cholangiocyte progenitors. • Oval cells as adult-type hepatocyte/cholangiocyte progenitors are most likely to be facultative stem cells, although cells with stem cell activity from extrahepatic sources may also operate in liver regeneration.

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