Liver Renewal: Detecting Misrepair and Optimizing Regeneration Mariana Verdelho Machado, MD, Anna Mae Diehl, MD  Mayo Clinic Proceedings  Volume 89, Issue 1, Pages 120-130 (January 2014) DOI: 10.1016/j.mayocp.2013.10.009 Copyright © 2014 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure In the normal liver, residual hepatocytes can replicate to regenerate hepatocytes that die. However, in chronic liver diseases, cytotoxic stresses cause hepatocytes to acquire a phenotype of replicative senescence. The injured and dying hepatocytes also send signals to neighboring progenitor cells and hepatic stellate cells to promote a wound-healing response. For example, wounded hepatocytes release morphogens that are known to promote fibrogenesis, such as hedgehog and Wnt ligands. In response to these factors, the hepatic stellate cell compartment becomes myofibroblastic and expands. Progenitor growth is also increased, inflammatory cells are recruited, and vasculogenesis is induced. The accumulating myofibroblasts, progenitors, and neovessels tend to intermingle within and along fibrous matrix, forming scar tissue. Scar formation occurs transiently during successful regeneration. However, when fibrogenic mechanisms are sustained or excessive, scarring becomes progressive and regeneration of functional hepatic parenchyma is compromised. Instead, the deregulated remodeling response promotes cirrhosis. The cirrhotic microenvironment, in turn, favors the outgrowth of malignant liver epithelial cells, thereby promoting hepatocarcinogenesis. Mayo Clinic Proceedings 2014 89, 120-130DOI: (10.1016/j.mayocp.2013.10.009) Copyright © 2014 Mayo Foundation for Medical Education and Research Terms and Conditions