A model of liver regeneration.

The network of interactions underlying liver regeneration is robust and precise with liver resections resulting in controlled hyperplasia (cell proliferation) that terminates when the liver regains its lost mass. The interplay of cytokines and growth factors responsible for the inception and termination of this hyperplasia is not well understood. A model is developed for this network of interactions based on the known data of liver resections. This model reproduces the relevant published data on liver regeneration and provides geometric insights into the experimental observations. The predictions of this model are used to suggest two novel strategies for speeding up liver mass recovery and a strategy for enabling liver mass recovery in cases where a resection leaves <20% of the liver that would otherwise result in complete loss of liver mass.

[1]  J. Ando,et al.  Differential regulation of urokinase-type plasminogen activator expression by fluid shear stress in human coronary artery endothelial cells. , 2004, American journal of physiology. Heart and circulatory physiology.

[2]  S. Poulsen,et al.  Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats , 1988, Hepatology.

[3]  N. Fausto.  Hepatocytes break the rules of senescence in serial transplantation studies. Is there a limit to their replicative capacity? , 1997, The American journal of pathology.

[4]  David C. Lee,et al.  Heparin-binding Epidermal Growth Factor-like Growth Factor Links Hepatocyte Priming with Cell Cycle Progression during Liver Regeneration* , 2005, Journal of Biological Chemistry.

[5]  J. Heath.  Principles of Cell Proliferation , 2001 .

[6]  J. Emond,et al.  Progressive necrosis after hepatectomy and the pathophysiology of liver failure after massive resection. , 1997, Surgery.

[7]  J. Darnell,et al.  Signalling: STATs: transcriptional control and biological impact , 2002, Nature Reviews Molecular Cell Biology.

[8]  J. Mead,et al.  Transforming growth factor alpha may be a physiological regulator of liver regeneration by means of an autocrine mechanism. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[9]  R. Taub,et al.  Rapid activation of the stat3 transcription complex in liver regeneration , 1995, Hepatology.

[10]  M. Sharpe,et al.  Scatter factor/hepatocyte growth factor is essential for liver development , 1995, Nature.

[11]  D. Houssin,et al.  Extent of hepatectomy in the rat. Evaluation of basal conditions and effect of therapy. , 1989, European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes.

[12]  A. Schönthal,et al.  Posttranscriptional regulation of c-fos mRNA expression. , 1987, Nucleic acids research.

[13]  A. Su,et al.  Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  N. Bucher,et al.  THE RATE OF INCORPORATION OF LABELED THYMIDINE INTO THE DEOXYRIBONUCLEIC ACID OF REGENERATING RAT LIVER IN RELATION TO THE AMOUNT OF LIVER EXCISED. , 1964, Cancer research.

[15]  P. Heinrich,et al.  Expression of suppressors of cytokine signaling during liver regeneration. , 2001, The Journal of clinical investigation.

[16]  P. Heinrich,et al.  Different protein turnover of interleukin-6-type cytokine signalling components. , 1999, European journal of biochemistry.

[17]  W. Heine,et al.  Regeneration of liver parenchyma under normal and pathological conditions. , 1971, Beitrage zur Pathologie.

[18]  M. Iwai,et al.  Increased secretion of tumour necrosis factor and interleukin 6 from isolated, perfused liver of rats after partial hepatectomy. , 2001, Cytokine.

[19]  J. Bruix,et al.  Tumor necrosis factor primes hepatocytes for DNA replication in the rat , 1998, Hepatology.

[20]  B. Fisher,et al.  A Portal Blood Factor as the Humoral Agent in Liver Regeneration , 1971, Science.

[21]  Jean S. Campbell,et al.  Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr41 , 2006, The Journal of Immunology.

[22]  C. Guguen-Guillouzo,et al.  TNFα‐mediated extracellular matrix remodeling is required for multiple division cycles in rat hepatocytes , 2005, Hepatology.

[23]  J. Albrecht,et al.  Evidence That Cyclin D1 Mediates Both Growth and Proliferation Downstream of TOR in Hepatocytes* , 2003, The Journal of Biological Chemistry.

[24]  N. Bucher,et al.  Regeneration of Rat Liver: Transfer of Humoral Agent by Cross Circulation , 1967, Science.

[25]  R. Pestell,et al.  Amino Acids Regulate Hepatocyte Proliferation through Modulation of Cyclin D1 Expression* , 2003, Journal of Biological Chemistry.

[26]  G. Michalopoulos,et al.  The processing and utilization of hepatocyte growth factor/scatter factor following partial hepatectomy in the rat , 2001, Hepatology.

[27]  C. Papasian,et al.  Bacterial DNA and Lipopolysaccharide Induce Synergistic Production of TNF-α Through a Post-Transcriptional Mechanism1 , 2001, The Journal of Immunology.

[28]  W. Heine,et al.  Regeneration of kidney parenchyma under normal and pathological conditions. , 1972, Beitrage zur Pathologie.

[29]  S. Thorgeirsson,et al.  Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Taub.  Liver regeneration: from myth to mechanism , 2004, Nature Reviews Molecular Cell Biology.

[31]  A. Brues,et al.  A quantitative study of cell growth in regenerating liver. , 1936 .

[32]  G. Michalopoulos,et al.  Immediate early detection of urokinase receptor after partial hepatectomy and its implications for initiation of liver regeneration , 1995, Hepatology.

[33]  R. Khokha,et al.  Thinking outside the cell: proteases regulate hepatocyte division. , 2005, Trends in cell biology.

[34]  S. Krane,et al.  Mutation in collagen‐I that confers resistance to the action of collagenase results in failure of recovery from CCl4‐induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  J. Mead,et al.  Induction of replicative competence ("priming") in normal liver. , 1990, Cancer research.

[36]  R. Cornell.  Gut-derived endotoxin elicits hepatotrophic factor secretion for liver regeneration. , 1985, The American journal of physiology.

[37]  T. Peterson,et al.  Fluid shear stress stimulates mitogen-activated protein kinase in endothelial cells. , 1995, Circulation research.

[38]  M. Moser,et al.  Immediate-Early Protooncogene Expression and Liver Function Following Various Extents of Partial Hepatectomy in the Rat , 2001, Digestive Diseases and Sciences.

[39]  Wei Li,et al.  STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration* , 2002, The Journal of Biological Chemistry.

[40]  G. Michalopoulos,et al.  Liver Regeneration , 1997, Journal of cellular physiology.

[41]  Yoshinobu Sato,et al.  Acute portal hypertension reflecting shear stress as a trigger of liver regeneration following partial hepatectomy , 1997, Surgery Today.

[42]  M. Alison.  Regulation of hepatic growth. , 1986, Physiological reviews.

[43]  N. Fausto,et al.  Mechanisms of liver regeneration and their clinical implications. , 2005, Journal of hepato-biliary-pancreatic surgery.

[44]  G. Michalopoulos,et al.  Expression of hepatocyte growth factor mRNA in regenerating rat liver after partial hepatectomy. , 1991, Biochemical and biophysical research communications.

[45]  M. Manns,et al.  The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. , 2005, The Journal of clinical investigation.

[46]  David Mangnall,et al.  The molecular physiology of liver regeneration following partial hepatectomy , 2003, Liver international : official journal of the International Association for the Study of the Liver.