Liver disorder:hepatocyte differentiation from iPS cells

As of July 2014, Regience concluded a joint research agreement to develop regenerative medical products for the treatment of cirrhosis using iPS cells with Osaka University and the National Institute of Biomedical Innovation (NIBIO).
Press release dated July 29th

Cirrhosis is a disease resulting the progression of chronic hepatic dysfunction which 400 to 500 thousand of people are contracted and will progress to liver cancer and liver failure. Liver transplantation is performed as the radical cure but there are many patients who cannot receive this treatment due to donor shortage. Therefore, development of an epoch-making therapy has long been waited, and regenerative medicine using iPS cells*1 that was developed by Professor Shinya Yamanaka at Kyoto University is particularly attracting attention as a treatment of liver disorders.
A large quantity of high-performance hepatocytes is necessary to execute hepatocyte transplantation. Hiroyuki Mizuguchi, Professor of Graduate School of Pharmaceutical Sciences of Osaka University and the visiting project leader of NIBIO, has succeeded in the development of technology for differentiating high-performance hepatocytes from iPS cells and in the development of technology for maintenance/augmentation of iPS cell-derived hepatic progenitor cells using laminin*2.
Regience is conducting a joint research of cirrhosis treatment based on the technology by Professor Mizuguchi which enables to supply a large quantity of hepatocytes. First of all, we are going to conduct a cell transplantation experiment to transplant iPS cell-derived hepatic progenitor cells to a liver disease model animal.

Regience aims for the development of regenerative medical products for liver disease and the development of corporate-initiated clinical trials at an early stage through this joint research.

  • *1:iPS cells: induced pluripotent stem cells. The re-programed stem cells using Yamanaka factors in somatic cells.
  • *2:Laminin: A part of extracellular matrix protein that constitutes the basal membrane of the organ.


Long-Term Self-Renewal of Human ES / iPS-Derived Hepatoblast-like Cells on Human Laminin 111-Coated Dishes
Kazuo Takayama, Yasuhito Nagamoto, Natsumi Mimura, Katsuhisa Tashiro, Fuminori Sakurai, Masashi Tachibana, Takao Hayakawa, Kenji Kawabata, Hiroyuki Mizuguchi
Stem Cell Reports. 2013 15; 1(4): 322–335.

Regenerative medicine for liver disease

Keio University

In April 2015, Regience has made a joint research agreement with Keio University, to develop regenerative medical products for liver disease using swine.

Press released at 9, April 2015

Recently, the studies for producing liver organoids from ES/iPS cells in vitro accelerate at a level of small animals. In the world, there were attempts to transplant them into patients of cirrhosis and metabolic disorders in liver. However, verifications using big animals considered a body size are essential to clinical applications. Also, for productizations of regenerative medicine for liver disease, it is thought there were problems as follows;

  1. Hepatocyte-like cells differentiated in vitro are extremely immature.
  2. In transplantation of isolated hepatocytes via portal vein, the cells hardly survive.
  3. Spheroid formation lead to high-performance of the grafts, but it is dangerous in clinical use because of increasing risks of embolization.
  4. In order to develop liver organoids as the liver tissues, it is necessary to transplant them into organisms.

Dr. Eiji Kobayashi, the representative of this joint research, specially appointed professor of Department of Organ Fabrication, Keio University, School of Medicine, is researching from various angles for applying the fabrication of human organ in clinical setting. In consideration of clinical application, his studies performed using swine because their body size is similar to human. Swine is getting more acceptable choice for experimental animal in preclinical research because of its biological and anatomical similarity to human. Additionally, it is easily accessed by many researchers because it has been miniaturized in late years. In this joint research, we are going to fabricate human liver tissue/organ in swine and examine whether the tissue/organ is capable of transplantation to human (Fig. 1).

Transplantation of hepatocytes is testing in many institutes in the world, however, one of common issues is that transplanted cells/tissues cannot survive for a long time. As above, it is possible to test transplantation methods with highly extrapolation using swine by its biological and anatomical similarity to human. Dr. Kobayashi has broad considerations for development of liver regenerative medicine including i) fabrication of whole liver organ in swine, ii) transplantation of liver buds, and iii) re-cellularization of human hepatocytes into decellularized liver matrix (Fig. 2).

Regience is going to develop products of regenerative medicine for liver disease in this joint research. We aim to produce applicable liver tissues for newborn infants with congenital inherited metabolic diseases, which is one of target disease proximate to clinical applications. In hepatic encephalopathy occurred from newborn infants with congenital inherited metabolic diseases, wastes and toxins produced in the body are not removed by hypofunction of liver, wastes/toxins reach to brain via blood stream and lead to decrease functions of brain; in serious cases, symptoms such as neurological sequelae or mental deficiencies are found. In newborn infants with congenital inherited metabolic diseases, they can prevent hepatic encephalopathy with the use of liver tissue and receive appropriate treatment immediately after the diagnosis of metabolic disorder.

We think, in the future, chronic lack of donor for all of liver diseases can completely solve, by developing the methods to produce whole liver in swine or in vitro using such as de-/re-cellulerization technique.

Figure 1 Liver fabrication using pig

Figure 2  A problem that need to be overcome in the liver regeneration