Patient stem cells used to make ‘heart disease-on-a-chip’ as testing platform for drugs

6-Jun-2014

Research could signify a big step forward for personalised medicine

Harvard scientists have merged stem cell and ‘organ-on-a-chip’ technologies to grow, for the first time, functioning human heart tissue carrying an inherited cardiovascular disease. The research could signify a big step forward for personalised medicine, as it is working proof that a chunk of tissue containing a patient’s specific genetic disorder can be replicated in the lab.

The work, published in Nature Medicine, is the result of a collaborative effort bringing together scientists from the Harvard Stem Cell Institute, the Wyss Institute for Biologically Inspired Engineering, Boston Children’s Hospital, the Harvard School of Engineering and Applied Sciences, and Harvard Medical School. It combines the ‘organs-on-chips’ expertise of Dr Kevin Kit Parker, and stem cell and clinical insights by Dr William Pu.

Using their interdisciplinary approach, the investigators modelled the cardiovascular disease Barth syndrome, a rare X-linked cardiac disorder caused by mutation of a single gene called Tafazzin, or TAZ. The disorder, which is currently untreatable, primarily appears in boys, and is associated with a number of symptoms affecting heart and skeletal muscle function.

The researchers took skin cells from two Barth syndrome patients, and manipulated the cells to become stem cells that carried these patients’ TAZ mutations. Instead of using the stem cells to generate single heart cells in a dish, the cells were grown on chips lined with human extracellular matrix proteins that mimic their natural environment, tricking the cells into joining together as they would if they were forming a diseased human heart. The engineered diseased tissue contracted very weakly, as would the heart muscle seen in Barth syndrome patients.

The investigators then used genome editing to mutate TAZ in normal cells, confirming that this mutation is sufficient to cause weak contraction in the engineered tissue. Delivering the TAZ gene product to diseased tissue in the lab corrected the contractile defect, creating the first tissue-based model of correction of a genetic heart disease.

‘You don’t really understand the meaning of a single cell’s genetic mutation until you build a huge chunk of organ and see how it functions or doesn’t function,’ said Parker. ‘In the case of the cells grown out of patients with Barth syndrome, we saw much weaker contractions and irregular tissue assembly. Being able to model the disease from a single cell all the way up to heart tissue, I think that’s a big advance.’

Furthermore, the scientists discovered that the TAZ mutation disrupts the normal activity of mitochondria in their role of making energy. However, the mutation didn’t seem to affect overall energy supply of the cells. In what could be a newly identified function for mitochondria, the researchers describe a direct link between mitochondrial function and a heart cell’s ability to build itself in a way that allows it to contract.

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His team is now using reactive oxygen species (ROS) therapy and gene replacement therapy in animal models of Barth syndrome to see if anything could potentially help human patients. The scientists are also using the ‘heart disease-on-a-chip’ as a testing platform for drugs that might be useful to treat the disorder.

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