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Patient stem cells used to make 'heart disease-on-a-chip'

May 12 2014, 14:01 IST
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SummaryHarvard scientists have for first time grown a functioning human heart tissue carrying inherited cardiovascular disease.

In a big step forward for personalised medicine, Harvard scientists have for the first time grown a functioning human heart tissue carrying an inherited cardiovascular disease by merging stem cell and 'organ-on-a-chip' technologies.

The research is working proof that a chunk of tissue containing a patient's specific genetic disorder can be replicated in the laboratory, scientists said.

In the study, researchers 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 - a technique pioneered by Harvard collaborator George Church - to mutate TAZ in normal cells, confirming that this mutation is sufficient to cause weak contraction in the engineered tissue.

On the other hand, delivering the TAZ gene product to diseased tissue in the laboratory corrected the contractile defect, creating the first tissue-based model of correction of a genetic heart disease.

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 Kevin Kit Parker, and stem cell and clinical insights by William Pu.

The scientists also discovered that the TAZ mutation disrupts the normal activity of mitochondria, often called the power plants of the cell for their role in making energy.

"The TAZ mutation makes Barth syndrome cells produce an excess amount of reactive oxygen species or ROS - a normal byproduct of cellular metabolism released by mitochondria - which had not been recognised as an important part of this disease," said Pu.

"We showed that, at least

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