Remarkable advances have been made recently in the area of liver regeneration. Even though liver regeneration after liver resection has been widely researched, new clinical applications have provided a better understanding of the process. Hepatic damage induces a process of regeneration that rarely occurs in normal undamaged liver. Many studies have concentrated on the mechanism of hepatocyte regeneration following liver damage. High mortality is usual in patients with terminal liver failure. Patients die when the regenerative process is unable to balance loss due to liver damage. During disease progression, cellular adaptations take place and the organ microenvironment changes. Portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy are relatively recent techniques exploiting the remarkable progress in understanding liver regeneration. Living donor liver transplantation is one of the most significant clinical outcomes of research on liver regeneration. Another major clinical field involving liver regeneration is cell therapy using adult stem cells. The aim of this article is to provide an outline of the clinical approaches being undertaken to examine regeneration in liver diseases.
The liver possesses the specific competence to return to a constant size within a short period after injury.
After liver resection, the residual liver responds by undergoing hyperplasia (
Usually hepatocytes are non-dividing (G0 phase) in the normal liver. After liver injury, they enter the G1 phase. Tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) are released from Kupffer cells, and these contribute to the initiation of the cell cycle (G0 to G1) by binding to their receptors.
Oval cells are detected after partial hepatectomy when hepatocyte proliferation is suppressed in the rat or mouse models. It is very difficult to find oval cell mediated liver regeneration in the chronic liver disease patients. Their origin is unclear, but there is considerable evidence that they derive from the biliary component.
Recent research for liver regeneration is focused on human liver disease treatment especially for various hepatectomy for chronic liver disease and hepatic tumors. For these innovative researches on liver regeneration, hepatectomy outcomes have markedly improved over recent decades.
Portal vein embolization (PVE) is the best example of how liver regeneration research has influenced clinical application. PHLF is associated with a small relative residual liver volume.
Living donor liver transplantation is state of the art of liver regeneration research. Even though wonderful clinical outcomes from Asian large volume centers, there are still obstacles to be overcome. In 2008, Ghobrial et al. examined donor morbidity following living donor liver transplantation. Overall complications were 38% (148 donors had a total of 220 complications). According to the Clavien grading system, there were 48% grade 1 complications, 47% grade 2, <4% grade 3 and 1.4% grade 4 (leading to death).
Understanding about liver regeneration has been made some progress for treating small-for size graft syndrome following living donor liver transplantation. Small-for-size graft syndrome is defined as long-lasting cholestasis and refractory ascites.
In 2008, Ikegami et al. summarized the reason of small-for-size syndrome and outlined potential solutions. The former involved graft size, quality, and flow as graft-related factors, and portal hypertension and the severity of the liver disease as recipient-related factors. Right lobe grafts, auxiliary transplants, and dual graft transplants were described as strategies for overcoming insufficient graft size. For poor graft quality, use of younger donors and donor diet programs for steatosis were possible strategies. Various shunt and graft operations were considered for excessive inflow and insufficient outflow drainage. Larger grafts and appropriate flow were considered ways of dealing with poor general recipient condition.
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) refers to in situ splitting and iatrogenic portal vein obliteration aimed at inducing rapid liver hypertrophy; it was first introduced by Hans Schlitt in 2007.
In 2007, Takahashi et al. generated pluripotent stem cells from adult human fibroblasts.
Tissue engineering can be a useful therapeutic option that combines cells, biological scaffolds and active molecules.
Liver regeneration has been well known for centuries, and in recent decades we have begun to understand its mechanism. Recent researches have focused on understanding liver regeneration after liver resection and liver transplantation. The use of innovative approaches could change strategies for treating liver dysfunctions such as PHLF and small-for-size graft syndrome. Liver regeneration has numerous applications. The use of PVO should permit the removal of large volumes of liver tissue with a diminished risk of liver failure. Hepatocyte transplantation could repopulate the liver of patients with inborn error metabolism. Moreover, regenerative therapy could provide innovative support for living donor transplantation. In the near future, we will be able to make artificial livers constructed from an individual's own cells. This would be the perfect way to support liver transplantation without the need for immunosuppressant drugs. In conclusion, the research of liver regeneration provides new strategies for the detection and treatment of a variety of liver diseases.
associating liver partition and portal vein ligation for staged hepatectomy
epidermal growth factor
hepatocyte growth factor
interleukin-6
international study group of liver surgery
post-hepatectomy liver failure
post-operative day
portal vein embolization
portal vein occlusion
transforming growth factor beta
tumor necrosis factor alpha
Year | First author | Contents |
---|---|---|
2011 [ |
Mortensen | Animal research on liver regeneration |
2010 [ |
Kandilis | Variable cell types and topographic differences |
2007 [ |
Michalopoulos | Molecular aspects of liver regeneration |
2006 [ |
Fausto | Molecular mechanism of liver regeneration |
2004 [ |
Black | Molecular aspects of liver regeneration |
2004 [ |
Zimmermann | Regulatory steps of liver regeneration |
2001 [ |
Kountouras | Liver regeneration after hepatectomy |
2000 [ |
Diehl | Molecular aspects of liver regeneration |
1997 [ |
Kay | Molecular aspects and clinical applications of liver regeneration |
1996 [ |
Taub | Genetic aspects of liver regeneration |
1996 [ |
Diehl | Signal regulation during liver regeneration |
1991 [ |
Fausto | Variable growth factors in liver |
1990 [ |
Leffert | Molecular aspects of liver regeneration |
1990 [ |
Michalopoulos | Molecular aspects of liver regeneration |
1986 [ |
Alison | Molecular aspects of liver regeneration |
Cytokine | Function |
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Tumor necrosis factor α (TNF-α) | After partial hepatectomy, expression of TNF-α is induced in Kupffer cells. |
It vitalize the transcription factor, nuclear factor κB (NF-κB). | |
The latter is an potent regulator of initiation of liver regeneration. | |
Interleukin-6 (IL-6) | IL-6 is increased after partial hepatectomy and serum levels are elevated soon after hepatectomy. |
It is mainly secreted by Kupffer cells and the LPS/MyD88 pathway regulate its expression. | |
Hepatocyte growth factor (HGF) | A fter partial hepatectomy, serum HGF level increase intensively within 1-3 hours. HGF activates receptor tyrosine kinase c-Met. |
It is a major hepatocyte mitogen. | |
Epidermal growth factor (EGF) family | EGF activates EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4. |
It provoke hepatocyte proliferation and is significant for survival after partial hepatectomy. | |
Fibroblast growth factors (FGFs) | FGFs activate FGF receptors (FGFR) 1–4. |
Vascular endothelial growth factor (VEGF) | VEGF controls angiogenesis and lymphangiogenesis by activating three receptor tyrosine kinases (VEGFR1-3). |
Insulin-like growth factors (IGFs) | IGF-I and IGF-II are strong mitogens. |
They bind to six insulin-like growth factor binding proteins (IGFBPs). | |
Transforming growth factor β (TGF-β) | TGF-β activates heteromeric receptor complexes containing type I and type II transmembrane receptors. |
It is a powerful suppressor for variable types of epithelial cells. | |
Activins | Activins activate heterodimeric receptor complexes consisting of type I and type II receptors. |
Activin A has a potential role in terminating the liver regeneration. |