Using stem cells to take an inside approach to fixing damaged livers

Often on the Stem Cellar we write about work that is in a clinical trial. But getting research to that stage takes years and years of dedicated work. Over the next few months we are going to profile some of the scientists we fund who are doing Discovery, or early stage research, to highlight the importance of this work in developing the treatments that could ultimately save lives.

 This first profile is by Pat Olson, Ph.D., CIRM’s Vice President of Discovery & Translation

liver

Most of us take our liver for granted.  We don’t think about the fact that our liver carries out more than 500 functions in our bodies such as modifying and removing toxins, contributing to digestion and energy production, and making substances that help our blood to clot.  Without a liver we probably wouldn’t live more than a few days.

Our liver typically functions well but certain toxins, viral infections, long-term excess alcohol consumption and metabolic diseases such as obesity and type 2 diabetes can have devastating effects on it.  Under these conditions, functional liver cells, called hepatocytes, die and are replaced with cells called myofibroblasts.  Myofibroblasts are cells that secrete excess collagen leading to fibrosis, a form of scarring, throughout the liver.  Eventually, a liver transplant is required but the number of donor livers available for transplant is small and the number of persons needing a functional liver is large.  Every year in the United States,  around 6,000 patients receive a new liver and more than 35,000 patients die of liver disease.

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willenbring photo

Dr. Holger Willenbring

Dr. Holger Willenbring, a physician scientist at UCSF, is one of the CIRM-funded researchers pursuing a stem cell/regenerative medicine approach to discover a treatment for patients with severe liver disease.  There are significant challenges to treating liver disease including getting fully multi-functional hepatocytes and getting them to engraft and/or grow sufficiently to achieve adequate mass for necessary liver functions.

In previous CIRM–funded discovery research, Dr. Willenbring and his team showed that they could partially reprogram human fibroblasts (the most common cell found in connective tissue) and then turn them into immature hepatocytes.  (see our Spotlight on Liver Disease video from 2012 featuring Dr. Willenbring.) These immature hepatocytes, when transplanted into an immune-deficient mouse model of human liver failure, were shown to mature over time into hepatocytes that were comparable to normal human hepatocytes both in their gene expression and their function.

This was an important finding in that it suggested that the liver environment in a living animal (in vivo), rather than in a test tube (in vitro) in the laboratory, is important for full multi-functional maturation of hepatocytes.  The study also showed that these transplanted immature human hepatocytes could proliferate and improve the survival of this mouse model of chronic human liver disease.  But, even though this model was designed to emphasizes the growth of functional human hepatocytes, the number of cells generated was not great enough to suggest that transplantation could be avoided

A new approach

Dr. Willenbring and his team are now taking the novel approach of direct reprogramming inside the mouse.  With this approach, he seeks to avoid the challenge of low engraftment and proliferation of transplanted hepatocytes generated in the lab and transplanted. Instead, they aim to take advantage of the large number of myofibroblasts in the patient’s scarred liver by turning them directly into hepatocytes.

Recently, he and his team have shown proof-of principle that they can deliver genes to myofibroblasts and turn them into hepatocytes in a mouse. In addition these in vivo myofibroblasts-derived hepatocytes are multi-functional, and can multiply in number, and can even reverse fibrosis in a mouse with liver fibrosis.

From mice to men (women too)

Our latest round of funding for Dr. Willenbring has the goal of moving and extending these studies into human cells by improving the specificity and effectiveness of reprogramming of human myofibroblasts into hepatocytes inside the animal, rather than the lab.

He and his team will then conduct studies to test the therapeutic effectiveness and initial safety of this approach in preclinical models. The ultimate goal is to generate a potential therapy that could eventually provide hope for the 35,000 patients who die of liver disease each year in the US.

 

 

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What’s the big idea? Or in this case, what’s the 19 big ideas?

supermarket magazineHave you ever stood in line in a supermarket checkout line and browsed through the magazines stacked conveniently at eye level? (of course you have, we all have). They are always filled with attention-grabbing headlines like “5 Ways to a Slimmer You by Christmas” or “Ten Tips for Rock Hard Abs” (that one doesn’t work by the way).

So with those headlines in mind I was tempted to headline our latest Board meeting as: “19 Big Stem Cell Ideas That Could Change Your Life!”. And in truth, some of them might.

The Board voted to invest more than $4 million in funding for 19 big ideas as part of CIRM’s Discovery Inception program. The goal of Inception is to provide seed funding for great, early-stage ideas that may impact the field of human stem cell research but need a little support to test if they work. If they do work out, the money will also enable the researchers to gather the data they’ll need to apply for larger funding opportunities, from CIRM and other institutions, in the future

The applicants were told they didn’t have to have any data to support their belief that the idea would work, but they did have to have a strong scientific rational for why it might

As our President and CEO Randy Mills said in a news release, this is a program that encourages innovative ideas.

Randy Mills, Stem Cell Agency President & CEO

Randy Mills, CIRM President & CEO

“This is a program supporting early stage ideas that have the potential to be ground breaking. We asked scientists to pitch us their best new ideas, things they want to test but that are hard to get funding for. We know not all of these will pan out, but those that do succeed have the potential to advance our understanding of stem cells and hopefully lead to treatments in the future.”

So what are some of these “big” ideas? (Here’s where you can find the full list of those approved for funding and descriptions of what they involve). But here are some highlights.

Alysson Muotri at UC San Diego has identified some anti-retroviral drugs – already approved by the Food and Drug Administration (FDA) – that could help stop inflammation in the brain. This kind of inflammation is an important component in several diseases such as Alzheimer’s, autism, Parkinson’s, Lupus and Multiple Sclerosis. Alysson wants to find out why and how these drugs helps reduce inflammation and how it works. If he is successful it is possible that patients suffering from brain inflammation could immediately benefit from some already available anti-retroviral drugs.

Stanley Carmichael at UC Los Angeles wants to use induced pluripotent stem (iPS) cells – these are adult cells that have been genetically re-programmed so they are capable of becoming any cell in the body – to see if they can help repair the damage caused by a stroke. With stroke the leading cause of adult disability in the US, there is clearly a big need for this kind of big idea.

Holger Willenbring at UC San Francisco wants to use stem cells to create a kind of mini liver, one that can help patients whose own liver is being destroyed by disease. The mini livers could, theoretically, help stabilize a person’s own liver function until a transplant donor becomes available or even help them avoid the need for liver transplantation in the first place. Considering that every year, one in five patients on the US transplant waiting list will die or become too sick for transplantation, this kind of research could have enormous life-saving implications.

We know not all of these ideas will work out. But all of them will help deepen our understanding of how stem cells work and what they can, and can’t, do. Even the best ideas start out small. Our funding gives them a chance to become something truly big.


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MIT Scientists Recreate Malaria in a Dish to Test Promising Drug Candidates

At the beginning, it feels like the flu: aches, pains and vomiting. But then you begin to experience severe cold and shivering, followed by fever and sweating—a cycle, known as tertian fever, that repeats itself every two days. And that’s when you know: you’ve contracted malaria.

Malaria is caused by Plasmodium parasites and spread to people through the bites of infected mosquitoes

Malaria is caused by Plasmodium parasites and spread to people through the bites of infected mosquitoes

But you wouldn’t be alone. According to the World Health Organization, nearly 200 million people, mostly in Africa, contracted the disease in 2013. Of those, nearly half a million—mainly children—died. There is no cure for malaria, and the parasites that cause the disease are quickly developing resistance to treatments. This is a global public health crisis, and experts agree that in order to halt its spread, they must begin thinking outside the box.

Enter Sangeeta Bhatia, renowned biomedical engineer from the Massachusetts Institute of Technology (MIT)—who, along with her team, has devised a quick and easy way to test out life-saving drug candidates that could give doctors and aid workers on the front lines fresh ammunition.

One of the key hurdles facing scientists has been the nature of the disease’s progression itself. Caused by parasites transmitted via infected mosquitos, the disease first takes hold in the liver. It is only after a few weeks that it enters the blood stream, causing symptoms. By then, the disease is so entrenched within the patient that complete eradication is extremely difficult. Even if the patient recovers, he or she will likely suffer relapses weeks, months or even years later.

The trick, therefore, is to catch the disease before it enters the blood stream. To that effect, several promising drugs have been put forth, and scientists are eager to test them out on liver tissue infected with malaria. Except that they can’t: liver tissue donors are few and far between, and lack the genetic diversity needed for large-scale testing.

Liver-stage malarial infection in iPSC-derived liver cells, eight days after infection. [Credit Ng et al.]

Liver-stage malarial infection in iPSC-derived liver cells, eight days after infection. [Credit Ng et al.]

So Bhatia and her team developed a new solution: they’d make the cells themselves. Reporting in today’s issue of Stem Cell Reports, the team describes how they transformed human skin cells into liver cells, by way of induced pluripotent stem cell (iPS cell) technology. Then, by infecting these cells with the malaria parasite, they could test a variety of drug candidates to see which worked best. As Bhatia explained:

“Our platform can be used for testing candidate drugs that act against the parasite in the early liver stages, before it causes disease in the blood and spreads back to the mosquito vector. This is especially important given the increasing occurrence of drug-resistant strains of malaria in the field.”

Bhatia has long been known for finding innovative solutions to longstanding issues in science and medicine. Just last year, she was awarded the prestigious Lemelson-MIT Prize in part for her invention of a paper-based urine test for prostate cancer.

In this study, the researchers bombarded malaria-infected liver cells with two drugs, called atovaguone and primaquine, each developed to treat the disease specifically at the liver stage.

The results, though preliminary, are promising: the cells responded well to both drugs, underscoring the value of this approach to testing drugs—an approach that many call “disease in a dish.”

The potential utility of “disease in a dish” studies cannot be understated, as it gives researchers the ability to screen drugs on cells from individuals of varying genetic backgrounds, and discover which drug, or drugs, works best for each group.

Shengyong Ng, a postdoctoral researcher in Bhatia’s lab, spoke of what this study could mean for disease research:

“The use of iPSC-derived liver cells to model liver-stage malaria in a dish opens the door to study the influence of host genetics on antimalarial drug efficacy, and lays the foundation for their use in antimalarial drug discovery.”

Find out more about how scientists use stem cells to model disease in a dish in our video series, Stem Cells In Your Face.