title: Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response.
abstract: METHODS
  In advanced liver damage, hepatic regeneration can occur through proliferation of a resident hepatic progenitor cell (HPC) population. HPCs are located within a designated niche in close association with myofibroblasts and bone marrow (BM) derived macrophages. Extra-cellular matrix (ECM) laminin invariably surrounds HPCs, but the functional requirement of this matrix-cell association is untested in vivo. Using the collagen Iα1((r/r)) mouse (r/r), which produces mutated collagen I resistant to matrix metalloproteinase degradation and has an exaggerated fibrotic response to liver injury, we test the relationship between collagen degradation, laminin deposition, and the HPC response.
  
  
  RESULTS
  Chronic fibrotic carbon tetrachloride (CCl₄) injury can induce a florid HPC response associated with dense laminin deposition. In the recovery phase after chronic CCl₄ injury, r/r mice have a markedly attenuated HPC response compared to wild-types, together with persistence of collagen I and failure to deposit ECM laminin. Similar results were found in r/r mice given the choline-deficient ethionine supplemented diet, another model of the HPC response. In cross-over sex-mismatched BM transplantation (BMT) experiments between r/r mice and wild-types, the blunted HPC response of r/r mice was not rescued by wild-type BMT and likewise not conferred on to wild-type recipients by r/r BMT, demonstrating that the attenuated HPC response in r/r mice is a property intrinsic to the liver.
  
  
  CONCLUSIONS
  Failure of ECM remodelling after chronic fibrotic liver injury hinders the ability of the liver to activate HPCs. Laminin-progenitor cell interactions within the HPC niche are a critical for HPC mediated regeneration.
authors.affiliation: Department of Medicine, St Mary’s Hospital Campus, Imperial College London, London, UK.
authors.forename: Yiannis N
authors.initials: YN
authors.lastname: Kallis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Robson
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fallowfield
authors.forename: Howard C
authors.initials: HC
authors.lastname: Thomas
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Alison
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldin
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D016026:Bone Marrow Transplantation; D002251:Carbon Tetrachloride; D002796:Choline Deficiency / Q000150:complications; D003094:Collagen / Q000378:metabolism; D005001:Ethionine / Q000008:administration & dosage; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D007797:Laminin / Q000172:deficiency; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D008115:Liver Regeneration / Q000502:physiology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013234:Stem Cells / Q000473:pathology*
chemical_list: D007797:Laminin; D003094:Collagen; D002251:Carbon Tetrachloride; D005001:Ethionine