The liver possesses the specific competence to return to a constant size within a short period after injury.1,2 We can observe this clinically in the form of regeneration after liver resection or liver transplantation, and after toxic liver injury. Liver regeneration involves hyperplasia of all the cell types of the liver. In humans, hapatocyte replication generally starts within a day of major hepatectomy, and replication of non-parenchymal cells, such as endothelial cells, Kupffer cells, and biliary cells begins somewhat later.3 Intensive research on liver regeneration has been carried out for several years (Table 1). But the molecular signals responsible for maintaining an original liver volume are unclear. However it stands to reason that the liver keeps up a delicate balance between cell loss and excess growth.4 Remarkable advancements that are directly relevant to clinical problems have been made in our understanding of liver regeneration. Moreover new experimental approaches have provided us much more information of hepatic failure and liver regeneration.5 The aim of this review is to survey recent progress in understanding liver regeneration. Greater understanding will lead to safer operations on living donors and on patients with huge or multiple liver masses. Furthermore it should provide to the development of new treatment strategies and diagnostic procedures for various liver diseases.

After liver resection, the residual liver responds by undergoing hyperplasia (Fig. 1).1 Upon partial hepatectomy, non-diving mature hepatocytes quickly reenter the cell cycle. Throughout proliferation, liver recover its own volume. There are two main proposals concerning the physiological triggers for liver regeneration.6 One is that the increased energy demand per unit liver volume after partial hepatectomy generates an early stress signal.7 The other is that liver regeneration is triggered by altered hemodynamic factors. Although there is a definite correlation between blood flow and liver regeneration, the definite role of blood flow in liver regeneration remain unclear.6 Similar liver regeneration can be initiated after several different hepatic injuries including viral and toxic hepatitis.

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.20 However post-hepatectomy liver failure (PHLF) remains one of the most dangerous and life-threatening complications of hepatectomy, and takes place in up to 10% of cases.21 A number of different criteria are used for PHLF. One of the most frequently used in clinical practice is the 50-50 criterion that combines a PT index <50% and serum total bilirubin >50 µmol/L (>2.9 mg/dL) on post-operative day (POD) 5.22 In 2011, the International Study Group of Liver Surgery (ISGLS) described the three grades of PHLF.23 This kind of criteria could be established because of marked increase of understanding of clinical aspect of liver regeneration potential in chronic liver disease patients.

Tissue engineering can be a useful therapeutic option that combines cells, biological scaffolds and active molecules.39 Three-dimensional (3-D) scaffolds play a critical role in tissue engineering by regulating cell functions and inducing the formation of new tissues and organs. They supply adequate space for the transplanted cells, as well as physical and biological signals that promote adhesion, migration, proliferation and differentiation, and they also gather the cells that have proliferated, and released matrices, into functional tissues and organs.40 In 2010, Ott et al. created an artificial biological lung from decellularized lungs. They made these lungs by detergent perfusion and succeeded in generating scaffolds that contained vasculature, airways and alveoli without cell. Thereafter they were able to successfully transplant the regenerated artificial lungs into the orthotopic position.41 In 2010, Uygun et al. demonstrated the architecture of a decellularized 3-D liver, as well as its functional vasculature and the original matrix composition. Furthermore, they achieved recellularization of the graft in vitro. This artificial liver was viable on its own.42 In 2013, Takebe et al. constructed a functional human organ from pluripotent stem cells. They generate functional human liver with vasculature from human induced pluripotent stem cells by transplantation of liver buds created in vitro.43 3-D printing refers to a variety of processes for making three-dimensional objects from a 3D models or other electronic data sources primarily through an additive process in which successive layers of material are laid down under computer control. In the near future, we should be able to generate bio-printed livers using 3D printing technology.

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.