Friday August 27 2010
Fibroblast skin cells were changed into liver cells
You will be able to “grow your own transplant liver in a lab within just five years,” says the Daily Mail.
This news story is based on research that demonstrated a method to develop skin cells into stem cells, which were then matured into liver cells. The researchers used this technique to develop lab-grown liver cells from patients with inherited liver diseases, which they hope might aid future research into diseases. They found that the new liver cells shared a number of characteristics with the patients' liver cells.
The method developed in this research looks likely to be an invaluable technique for creating cell cultures that could be experimented on in the lab. However, this research did not aim to investigate how a fully-functional liver or transplantable cells could be grown in a lab, both of which are years away.
Where did the story come from?
The study was carried out by researchers from the University of Cambridge and funded by the Wellcome Trust, the Medical Research Council and the Biomedical Research Centre of the Cambridge Hospitals National Institute for Health Research. It was published in the peer-reviewed Journal of Clinical Investigation.
News reports generally covered this research accurately. However, the headline featured in the Daily Mail (“Grow your own transplant liver in a lab within just five years”) is misleading as this research does not suggest that the techniques involved could be used for this purpose.
What kind of research was this?
This was a laboratory study that aimed to develop a method for converting human skin cells into liver cells. The researchers induced the skin cells to become a type of stem cell called “inducible pluripotent stem cells”. These can develop into different types of cells when provided with appropriate chemicals, such as growth-inducing (growth factor) substances.
The researchers focused on whether it would be possible to generate these stem cells from people with inherited (i.e. genetic) metabolic disorders of the liver. This group of diseases affect key proteins in the liver. These patients may be treated with a liver transplant but this surgery carries risks.
In this study, the researchers wanted to see whether skin cells taken from these liver disease patients could be converted into liver cells displaying the characteristic problems seen in the patients’ natural liver cells. If successful, the technique could be used to produce cell culture models, which could then be used to understand the mechanisms of the disease and to help develop new therapies.
What did the research involve?
The researchers took skin samples from seven volunteers with inherited liver diseases and three healthy control patients, and isolated skin cells called fibroblasts from this tissue.
The fibroblast skin cells were genetically modified to introduce active copies of the human genes OCT4, SOX2, c-Myc and KLF4 into the cells to make them into inducible pluripotent stem cells (iPS). These iPS cells were then grown in the laboratory. Where possible, three iPS cell lines per individual were grown to look at how much variation there would be in the process of stem cells developing into liver cells.
To make the cells develop into liver cells (differentiate) the researchers treated them with a sequence of chemicals, including growth factors and other proteins. The cells were treated with five different rounds of chemical cocktails over a period of approximately 25 days. These chemicals caused the iPS cells to first develop into endoderm cells (a type of cell normally found in embryo development), and then into more “liver-like” hepatic endoderm cells. These immature cells were finally matured into liver cells.
To check whether the stem cells had successfully developed into liver cells, the researchers looked at whether the cells produced a protein called albumin, which is typically produced by liver cells. They also examined whether they had the same appearance as liver cells, and whether they could store the chemical glycogen and break down drugs as the liver does.
What were the basic results?
The researchers found that 80% of the cells produced by their technique were making albumin, suggesting that these were liver-like cells. The cells were also able to perform the other liver cell functions that the researchers assessed. However, further assessment of the gene activity in the cells found that the cells were not quite fully mature and were assessed to be developmentally somewhere between the liver cells of a four-month-old foetus and adult liver cells.
They found that out of 20 iPS cell lines made from 10 individuals, 18 of these were able to differentiate into liver cells. The researchers then looked at whether the liver cells that they had made from the skin cells of the liver patients showed the same properties and defects found in the patients’ own livers.
They first examined the cells developed from an individual who had a mutation in a gene called A1ATD, which causes the accumulation of a protein called α1-antitrypsin in their liver cells. They found that this protein also accumulated in the liver cells developed from patients with the condition but not the liver cells from healthy control individuals.
Patients with familial hypercholesterolemia have high levels of LDL cholesterol. This is because they have a mutation affecting a protein called the LDL receptor, which would normally remove LDL circulating in the blood. The liver cells produced from the skin of an individual with this disease also lacked the LDL receptor protein.
Finally, they examined the liver cells produced from a person with glycogen storage disease type 1a, a condition that causes problems regulating sugar levels and abnormal accumulation of glycogen, the glucose storage molecule, within their liver cells. The liver cells derived from these individuals showed the same accumulations of glycogen and also replicated some other features of the disease, such as accumulation of fat and excessive production of lactic acid.
How did the researchers interpret the results?
The researchers say that inducible pluripotent stem cells (iPS) have been used to make cell culture models for a limited number of rare neurological diseases, but their research has shown that it is possible to also use this technique for non-neurological diseases, such as inherited metabolic diseases of the liver.
They then say that they have demonstrated that “human iPS cell-derived [liver cells] can be generated from multiple patients of varied genetic and disease backgrounds”. They also say that their system is “an efficient methodology for the early-stage safety and therapeutic screening of liver-targeted compounds of potential relevance to the pharmaceutical industry”.
This laboratory study has developed a method to produce liver cells from skin cells by producing inducible stem cells. The study showed the potential of this technique to produce cell culture models of inherited liver diseases. As the researchers point out, this is likely to be a useful tool to learn more about these diseases and screen for useful drugs.
However, this research was not done with the intention of growing transplantable livers, as suggested by the Daily Mail. A liver is comprised of a complex tissue of different types of cell and it has not been investigated whether the cells developed here could have the potential to be transplanted.
This is promising preliminary research that may lead to advances in the understanding of inherited liver diseases and in treatments for these conditions. The next step would be to test the processes developed in this small study on a larger number of patients to further investigate the cells generated and their potential for developing cell lines for research.