April 25, 2012

Teaching old cells new tricks


Stem cells. Credit: Candy Cho

April 25, 2012 in Medical research

Much hyped by the media, stem cells have tremendous power to improve human health. As part of the Cambridge Stem Cell Initiative, Dr Ludovic Vallier’s research in the Anne McLaren Laboratory for Regenerative Medicine shows how stem cells can further our understanding of disease and help deliver much-needed new treatments.

How do you study a human disease that has no equivalent in animals and where the human cells in question are so hard to grow outside the body they cannot be tested in the laboratory? The answer, until now, was with great difficulty. But by using a new stem cell technique, that is set to change.

Dr. Ludovic Vallier, who holds an MRC Senior Fellowship in the Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery at Cambridge in collaboration with Professor David Lomas (Cambridge Institute for Medical Research and Department of Medicine), works on a group of devastating genetic diseases affecting the liver.

“We target metabolic diseases of the liver, diseases such as alpha 1 antitrypsin deficiency. It’s one of the most common single genetic disorders and the protein it affects – which is only produced by the liver – is really important because it controls activity of elastase in the lung. Without this control, people develop serious lung problems and the disease also affects the liver, so these patients develop liver failure,” he explained.

The problem is that these diseases cannot be studied in vitro – in a dish – in the laboratory, he said: “You can’t take cells from the liver of these very sick patients, and if you could they wouldn’t grow, which means you don’t have any way of screening drugs that could help treat these diseases.”

Without effective drugs, the only current treatment is a liver transplant. “There is a huge shortage of organs and transplantation involves taking immunosuppressive drugs, which is heavy treatment especially in already fragile patients,” Dr. Vallier said. “And the disease is progressive so it’s very complicated to manage.” Understandably, Dr. Vallier is excited that a new method of producing stem cells developed in Japan has given him and other researchers a way of studying these diseases and screening potential drugs to treat them.

“The new technology consists of taking cells from skin and reprogramming them so that they become stem cells – cells that are capable of proliferating and differentiating into almost all tissue types,” he said.

This reprogramming means a cell with a previously fixed identity can be taught a new one – in this case taking skin cells and reprogramming them to become liver cells. When the skin cells come from a patient with liver disease, these skin-turned-liver cells also have the disease, making them ideal for studying the disease and screening potential drugs to treat it.

According to Dr. Vallier: “Because we can generate liver cells that mimic the disease of the original patient in vitro, that allows us to do basic studies that were impossible by biopsy or primary culture and also to do drug screening.” And because the skin cells can come from a whole range of people, it gives researchers access to a broad diversity of patients as well as overcoming some of the ethical concerns associated with embryonic stem cells.

“That’s a very important step because it solves the problems associated with a limited stock of stem cells,” he said, “and because it’s a simple method, it’s easily accessible to a wide number of laboratories.”

Showing this can be done in a small number of liver patients in Cambridge is an important proof of concept, and supports the possibility that a similar approach might be applicable to a wide range of other serious diseases that still lack effective treatments, including neurodegenerative diseases such as Parkinson’s and Alzheimer’s Disease as well as heart diseases.

And Cambridge – which now has almost 30 groups doing stem cell research and strong links between academic researchers and clinicians – is perfectly positioned to make the most of this new technique.

“The Laboratory for Regenerative Medicine is starting to become an expert in this disease modelling and we are all part of a larger consortium, the Cambridge Stem Cell Initiative (SCI),” said Dr. Vallier. “Together, we are putting together resources and scientific interest to really develop stem cells and their clinical application. The SCI is a unique consortium because it brings together a wealth of complementary expertise.”

While this first revolution involves in vitro disease modelling and drug screening, Dr. Vallier hopes this work will ultimately lead to personalized cell-based therapies where liver cells reprogrammed from a patient’s own skin cells could be used in place of a liver transplant. “It will take time for us to assess this clinical use and show that it is safe as well as effective,” he explained, “but if you ask me again in five years I should be able to tell you whether we are going to do it.”

Provided by University of Cambridge (news : web)


EASL 2012: Nonalcoholic Fatty Liver Disease Raises Liver Cancer Risk


From Medscape Medical News


Daniel M. Keller, PhD

April 25, 2012 (Barcelona, Spain) — A study with a large multicenter cohort has shown that nonalcoholic fatty liver disease (NAFLD) is a predisposing factor for hepatocellular carcinoma (HCC) in the absence of other liver diseases, and frequently without cirrhosis.

Here at the International Liver Congress 2012, Helen Reeves, BMedSci, BM, PhD, senior lecturer and honorary consultant gastroenterologist at Newcastle Hospitals in the United Kingdom, presented evidence that obesity is a worldwide problem and, as a result, the prevalence of NAFLD is rising.

Dr. Reeves spoke on behalf of the Fatty Liver Inhibition of Progression consortium, which was formed in January 2010 to address the problem. A central goal of the consortium is to create an "observatory" of HCC, NAFLD, and metabolic syndrome to characterize the diseases with high-quality data and sample collection.

The consortium has been collecting data for 3 years on patients with HCC and no other liver disease and who imbibe less than 50 g/day of alcohol. Unless the features of metabolic syndrome or NAFLD were present on liver histology or ultrasound, cases were considered cryptogenic.

A Minority of Cases Are Cryptogenic

"The fact is that only very few of these patients develop their hepatocellular cancer in the absence of metabolic syndrome, so just 20 of 221, which is 9%, had no metabolic risk factor," Dr. Reeves reported. Of the 201 remaining cases, 187 had metabolic syndrome risk factors, 66 had fatty liver diagnosed on ultrasonography, and 37 had fatty liver diagnosed on liver biopsy.

Alcohol consumption appeared to play a minor role at most. Fifty-five percent of participants rarely or never drank alcohol, 33% drank moderately in the past but no longer drink, and only 12% consume alcohol now but not more than 50 g/day.

Mean age at HCC diagnosis was 69 years, almost 4 times as many men as women were diagnosed, and fatty liver was previously diagnosed in 50% of the cohort. HCC was detected with scheduled monitoring in 48%; for most of the rest, it was detected with ultrasound for other reasons or from symptoms.

A single liver nodule was detected in 58% of the cohort, and 75% had preserved liver function (Child-Pugh grade A). Dr. Reeves said that despite the high prevalence of preserved liver function, 55% of the participants were graded as Barcelona Clinic Liver Cancer stage C or D, indicating symptomatic disease at the time of presentation.

"Forty-three percent developed their cancer in the absence of cirrhosis," Dr. Reeves told the delegates. The ratio of men to women was similar in those with and without cirrhosis, as was body mass index and the prevalence of diabetes. Still under analysis are the alcohol and smoking history of the cohort.

"What was significantly different was the size of the largest nodule.... [It] was significantly greater in those who did not have cirrhosis," she explained (30 vs 48 mm; P < .001). Patients with cirrhosis were more likely to have encephalopathy at the time of diagnosis than patients without cirrhosis (12% vs 3%; P = .04), and trended toward more ascites (33% vs 18%, P = .062).

Only about 10% of the patients received no definitive treatment for their liver cancer and were referred for best supportive palliative care. For the rest, only a few received liver transplants, but many received radiofrequency ablation, transarterial chemoembolization, medical therapy with sorafenib, or other treatment.

Dr. Reeves concluded that NAFLD is a predisposing condition for HCC in the absence of other liver diseases, and that NAFLD-associated HCC often occurs in the absence of cirrhosis. She said many of the patients were eligible for potentially curative therapies, and the consortium will continue to follow this cohort to observe outcomes.

Mark Thursz, MBBS, MD, secretary general of the European Association for the Study of the Liver and professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, told Medscape Medical News that, ironically, there is good news for patients with hepatitis C, in that several new drugs are coming along. "You can see cures just around the corner for high proportions of patients. Nonalcoholic fatty liver is much more difficult to deal with. It's quite difficult to change people's lifestyles."

He noted that NAFLD is now the leading cause of liver disease in North America, and will be in Europe before too long. "The fact that people are developing cancer before they develop cirrhosis — that's a concern because our current guidelines tell us we should be instituting surveillance programs for cancer in cirrhotic patients," Dr. Thursz said. "Extending that into precirrhotic patients is going to be quite challenging to resources, and the selection of patients is then going to be really critical."

He said the risk factors for NAFLD are well known and include abdominal fat, diabetes (or at least insulin resistance), low high-density-lipoprotein cholesterol, and high low-density-lipoprotein cholesterol.

"We can't predict with any accuracy which individual patient has progressive disease, as opposed to pure fat in the liver," he said.

There is no noninvasive way to tell if a patient has pure steatosis, has fat and inflammation, or has fat, inflammation, and fibrosis. "It's the latter group that is at risk" for HCC, he warned.

Dr. Thursz and Dr. Reeves have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 5. Presented April 19, 2012.


More EASL 2012 Conference Coverage from Barcelona


Provided By Clinical Care Options (All links open into new windows)

Highlights From EASL 2012

Source: CCO Independent Conference Coverage of the 2012 Annual Meeting of the European Association for the Study of the Liver*

*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.

Capsule Summaries

Disclaimer: The materials published on the Clinical Care Options Sites reflect the views of the reviewers or authors of the CCO material, not those of Clinical Care Options, LLC, the accredited provider, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials