Stem cells are the most famous examples of regenerative medicine.© pinkeyes/Shutterstock
New treatments for liver disease are the goal of Takahiro Ochiya, of Tokyo Medical University, and his work with Evia Life Sciences, a US-based company backed by Octave Ventures that he co-founded that focuses on regenerative medicine using stem cells.
Transplantation of liver tissue from living donors has been one of the most successful approaches for severe liver disease. However, explains Ochiya, the donor has a high risk of complications and recipients must take immunosuppressive drugs for the rest of their lives. Furthermore, there is a huge shortage of liver donors.
A more recent approach is transplantation of mature liver cells, known as hepatocytes. “The problem is obtaining sufficient quantities of fully functioning hepatocytes,” says Ochiya. “The solution we are exploring is to transplant liver progenitor cells.”
So far, Ochiya and his team have shown that mouse and rat hepatocytes extracted from livers, even damaged ones, can be reprogrammed into proliferative cells in vitro using a combination of low molecular weight compounds. The results were published in Cell Stem Cell in 2017. The cells, known as chemically-induced liver progenitors (CLiPs), can be transplanted back into the rodent’s liver via the portal vein or the spleen. The cells show characteristic liver-specific functions and only small numbers are needed to repopulate damaged livers with an efficiency of up to 90%.
Takahiro Ochiya and a colleague contemplate hepatocytes.© Evia Life Sciences Inc.
“This kind of reprogramming happens naturally in the injured liver when minor damage occurs,” says Ochiya. “However, major injury like long-term virus infection, alcoholic damage and drug damage may need more drastic measures.”
The small molecules used, which are inhibitors of regulatory pathways, are key to the technique. “Identifying the physiological mechanisms and molecules involved in natural liver reprogramming and regeneration is one of our ultimate goals,” says Ochiya.
The team has then extended the same approach to generate adult human CLiPs from infant donors, publishing their results in eLife in 2019. In collaboration with Professor Susumu Eguchi from Nagasaki University, work is underway to investigate whether human CLiPs can be cultured from the mature hepatocytes of patients with severely cirrhotic livers.
Another promising new line of research is the use of extracellular vesicles derived from human CLiPs to regenerate fibrotic livers. These membrane-bound vesicles are released from many types of cells and contain a mixture of proteins, nucleic acids, lipids, and various metabolites.
In the meantime, the team has grown hepatocyte progenitors into functioning miniature livers ex vivo. Under the right conditions, the cells differentiated into the two main cell types found in the liver, hepatocytes that carry out metabolic functions, and cholangiocytes, the cells that line the bile ducts. As they described in Nature Communications in 2021, the network of cholangiocytes in the hepatocyte clusters was functionally connected as a biliary network. Ochiya says the organoids will be useful for research into liver injuries and are likely to have utility in testing the effect of new drugs on the liver.