|Title||Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response.|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Kallis YN, Robson AJ, Fallowfield JA, Thomas HC, Alison MR, Wright NA, Goldin RD, Iredale JP, Forbes SJ|
|Date Published||2011 Apr|
|Keywords||Animals, Bone Marrow Cells, Bone Marrow Transplantation, Carbon Tetrachloride, Choline Deficiency, Collagen, Ethionine, Extracellular Matrix, Female, Laminin, Liver Cirrhosis, Experimental, Liver Regeneration, Macrophages, Male, Mice, Mice, Inbred C57BL, Stem Cells|
BACKGROUND AND 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.
CONCLUSION: 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.
|Grant List||G0600033 / / Medical Research Council / United Kingdom |
G84/6205 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom