July 3, 2013

expert reaction to iPS cells used to build a new liver

A Nature paper described how induced pluripotent stem (iPS) cells were used to make a functional human liver. 

Dr Dusko Ilic, Reader in Stem Cell Science, Kings College London, said:

“The authors employed a novel strategy of recapitulating development – they mixed together three cell types that coexist during liver organogenesis: hepatic endoderm cells, mesenchymal stem cells and endothelial cells. Mimicking a natural environment paid off and the liver buds generated in a culture dish were functional and mature enough to rescue drug-induced lethal liver failure in a mouse model.

“The strategy is very promising, and represents a huge step forward. Although the promise of an off-shelf-liver seems much closer than one could hope even a year ago, the paper is only a proof-of-concept. There is much unknown and it will take years before it could be applied in regenerative medicine. However, application in testing hepatotoxicity and drug metabolism in preclinical stage might be more imminent.”

Dr Matthew Smalley, Senior Lecturer, Cardiff University’s European Cancer Stem Cell Research Institute, said:

“I think this is a very exciting study. The authors have shown that, importantly, the transplanted liver buds not only produce liver-specific proteins but can also detoxify test compounds, which is key for restoring function in patients with failing livers. The route of transplantation still needs to be optimised for humans and safety and efficacy need to be demonstrated in patients, as well as long term function of the graft. Furthermore, not all patients may be suitable for this approach. Nevertheless, the study holds out real promise for a viable alternative approach to human organ transplants.”

Professor Chris Mason, Chair of Regenerative Medicine Bioprocessing, UCL, said:

“The greatest impact of iPS cell-liver buds may not be as cell therapies, where the practicalities of expanding liver buds in patients to a meaningful clinical size with an adequate blood supply will be highly challenging, but for improved drug development.  Presently to study the metabolism and toxicology of potential new drugs, human cadaveric liver cells are used; unfortunately these are only available in very limited quantities – insufficient for routine early stage R&D. However, from Takebe’s data, mice transplanted with human iPS cell-liver buds might help developers predict drug metabolite profiles for patients and thus enable early stage detection of unwanted side effects rather than later during clinical trials, or worse, after the drug enters routine clinical practice. For example, troglitazone, a Type 2 diabetes drug, that was withdrawn due to adverse liver effects.”

Professor Stuart Forbes, Professor of Transplantation and Regenerative Medicine, MRC Centre for Regenerative Medicine, University of Edinburgh, said:

“This is an exciting advance in the field where human iPSCs have been grown with vascular and other cells and coaxed into forming hepatocyte-like cells. The main finding is that the cells had a degree of self-organising ability to form 3D vascular structures that have been termed liver buds. The stem cell derived hepatocytes have some of the functions of mature hepatocytes and were capable of metabolising some drugs – a hallmark of liver cells.

“Whilst the title of the paper is ‘functional human liver’ these liver buds do not contain the biliary structures or immune cells that characterise real human liver. The biliary cells are the fine tubes that form a complex network around hepatocytes and drain the toxins from the hepatocytes out of the liver into the gut – without this network it is hard to see how these small buds could replace the liver’s function for more than a short time.

“Furthermore real livers contain large numbers of immune cells that help to filter and deal with the blood from the gut as the liver is the first organ that the blood from the gut meets. Although exciting there is still a lot more research needed before this approach could be applied to patients with liver disease. The liver buds were small and scaling up to a ‘human relevant size’ may be a challenge, as will creating a true liver structure. A further issue is that we are not clear about the long term stability of these stem cell derived cells within a recipient – this would need to be proven before clinical use could be envisaged.”

Professor Malcolm Alison, Professor of Stem Cell Biology, Barts Cancer Institute, Queen Mary University of London, said:

“The human liver evolves from a group of cells (endoderm) that line the embryonic intestinal wall. Hideki Taniguchi and colleagues have recapitulated this process in the lab by chemically inducing the partial differentiation of iPSC (induced pluripotent stem cells) to these hepatocyte-committed endodermal cells. Then, to create 3-D structures (liver buds) resembling early human liver, the committed endodermal cells were cultured with connective tissue cells and cells that line blood vessels. When transplanted into immunodeficient mice, the liver buds matured, the human blood vessels connected to the mouse host’s blood vessels, and they functioned as mature human hepatocytes. Mice subjected to an anti-cancer drug targeted to the mouse liver died of liver failure, but those mice also bearing the human liver buds invariably survived. This is an important proof-of-concept demonstration that transplantation of a lab-grown 3-D vascularized organ may treat cases of organ failure, applicable to liver, but the same principles could be extended to other complex organs such as the kidney.

“This study has made a major step forward in improving the effectiveness of liver cell transplantation for treating acute liver failure. Human mature liver cells transplanted on their own can fail to thrive, but if immature liver cells are first combined with their normally nurturing supportive cells they can mature in the transplanted host and function efficiently.  This science opens up the distinct possibility of being able to create mini-livers from the skin cells of a patient dying of liver failure, and when transplanted would not be subjected to immune rejection as happens with conventional liver transplants today.”

Dr Paul De Sousa, Reader, Centre for Regenerative Medicine, University of Edinburgh, said:

“The achievement is noteworthy for its demonstration of the potential of different cells originating from human pluripotent stem cells to spontaneously and crudely organise into liver-like tissue, as would normally only occur in a developing animal. At present it is not possible to control the composition of the cells in the spontaneously formed tissue, which could also harbour undifferentiated induced pluripotent stem cells with a potential to form tumours. Translation of this work into clinical practice in the future will still require integration of this accomplishment with technologies which can more precisely control the composition and organisation of cells within tissue. This could include 3-Dimensional printing of purified cell types onto supportive scaffolds in order to produce a more standardisable product. This could also benefit function.”

‘Vascularized and functional human liver from an iPSC-derived organ bud transplant’ by Takanori Takebe et al., published in Nature on Wednesday 3 July.