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.
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.
Authors: Morten A Karsdal; Tina Manon-Jensen; Federica Genovese; Jacob H Kristensen; Mette J Nielsen; Jannie Marie B Sand; Niels-Ulrik B Hansen; Anne-Christine Bay-Jensen; Cecilie L Bager; Aleksander Krag; Andy Blanchard; Henrik Krarup; Diana J Leeming; Detlef Schuppan Journal: Am J Physiol Gastrointest Liver Physiol Date: 2015-03-12 Impact factor: 4.052
Authors: Jan Best; Paul Manka; Wing-Kin Syn; Laurent Dollé; Leo A van Grunsven; Ali Canbay Journal: Hepatobiliary Surg Nutr Date: 2015-02 Impact factor: 7.293
Authors: Thomas G Bird; Wei-Yu Lu; Luke Boulter; Sabrina Gordon-Keylock; Rachel A Ridgway; Michael J Williams; Jessica Taube; James A Thomas; Davina Wojtacha; Adriana Gambardella; Owen J Sansom; John P Iredale; Stuart J Forbes Journal: Proc Natl Acad Sci U S A Date: 2013-04-01 Impact factor: 11.205