Blood vessel in a dish clue to Marfans

03 December 2016

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Cambridge scientists have developed a technique to turn skin into blood vessel muscle cells to uncover new treatments for arterial diseases including Marfans Syndrome.

About one person in every 5000 inherits a faulty copy of the fibrillin-1 gene that causes Marfans. Those affected by the disease tend to be taller, with longer than average arms and fingers.

Famously, Abraham Lincoln was said to have had the syndrome. Apart from external anatomical effects, the disease is also associated with a ballooning of the base of the main blood vessel leading out of the heart, the aorta, which can rupture catastrophically and fatally - in some people.

Why this occurs, though, and how best to manage patients with the disease - apart from resorting to surgery - is unclear.

Now a team of Cambridge scientists, led by cardiologist Sanjay Sinha, have developed a technique to recreate in a dish the very disease process going on in a patient, using the patient's own cells.

Writing in Nature Genetics, the team first take a skin biopsy from a patient. Cells called fibroblasts are harvested from the biopsy and genetically re-programmed to turn them into entities called iPS cells. These are stem cells resembling cells found very early in a developing embryo and, cultured under the right conditions, they can be fooled into believing they are back in a developing embryo.

After about 3 weeks of being supplemented with the right cocktail of growth factors, the stem cells turn into smooth muscle cells identical to those found in the patient's aorta.

"In all respects the cells are identical to the ones the patient has inside them," says Sinha. "And they show all the same abnormalities as the patient has, in terms of cell stiffness, loss of the extracellular matrix material that binds them together, and they also die off more readily."

The breakthrough matters because, rather than relying on animal models of disease, which can sometimes be misleading, it recreates the genuine human condition and very reproducibly, making experiments much easier to carry out.

It's already led the team to a greater level of understanding as to why patients with Marfan Syndrome develop changes in the aorta.

"The cells here produce a lot of the fibrillin gene product," explains Sinha. "In our experiments, if there is too little of it we see an increase in activity of a protein called p38, which seems to trigger the muscle cells to die."

It's the steady loss of muscle from the wall of the artery that makes it bulge and eventually burst. "Fortunately, there are some drugs already out there, which have been developed for other diseases but which block this pathway," says Sinha. So we can now test those agents in our cultured cells to see whether they might work in Marfan patients."

The new cell culture system, Sinha is keen to emphasise, has powerful potential beyond just Marfans.

"Heart disease kills one person in three, and there are lots of genes that we know affect your risk of the disease, but we don't know how. With this we can test them, and discover potential new therapies..."

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