Stem cell-based gut-on-a-chip: a new path to personalized medicine

“Personalized medicine” is a trendy phrase these days, frequently used in TV ads for hospitals, newspaper articles about medicine’s future and even here in the Stem Cellar. The basic gist is that by analyzing a patient’s unique biology, a physician can use disease treatments that are most likely to work in that individual.

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Emulate’s Organ-on-a-Chip device.
Image: Emulate, Inc.

This concept is pretty straight-forward but it’s not always clear to me how it would play out as a routine clinical service for patients. A recent publication in Cellular and Molecular Gastroenterology and Hepatology by scientists at Cedars-Sinai and Emulate, Inc. paints a clearer picture. The report describes a device, Emulate’s Intestine-Chip, that aims to personalize drug treatments for people suffering from gastrointestinal diseases like inflammatory bowel disease and Chrohn’s disease.

Intestine-Chip combines the cutting-edge technologies of induced pluripotent stem cells (iPSCs) and microfluidic engineering. For the iPSC part of the equation, skin or blood samples are collected from a patient and reprogrammed into stem cells that can mature into almost any cell type in the body. Grown under the right conditions in a lab dish, the iPSCs self-organize into 3D intestinal organoids, structures made up of a few thousand cells with many of the hallmarks of a bona fide intestine.

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Miniature versions of a human intestinal lining, known as organoids, derived from induced pluripotent stem cells (iPSCs).
Image: Cedars-Sinai Board of Governors Regenerative Medicine Institute

These iPSC-derived organoids have been described in previous studies and represent a breakthrough for studying human intestinal diseases. Yet, they vary a lot in shape and size, making it difficult to capture consistent results. And because the intestinal organoids form into hollow tubes, it’s a challenge to get drugs inside the organoid, a necessary step to systematically test the effects of various drugs on the intestine.

The Intestine-Chip remedies these drawbacks. About the size of a double A battery, the Chip is made up of specialized plastic engineered with tiny tunnels, or micro-channels. The research team placed the iPSC-derived intestinal organoid cells into the micro-channels and showed that passing fluids with a defined set of ingredients through the device can prod the cells to mimic the human intestine.

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Cells of a human intestinal lining, after being placed in an Intestine-Chip, form intestinal folds as they do in the human body. Image: Cedars-Sinai Board of Governors Regenerative Medicine Institute

The Intestine-Chip not only looks like a human intestine but acts like one too. A protein known to be at high levels in inflammatory bowel disease was passed through the microchannel and the impact on the intestinal cells matched what is seen in patients. Clive Svendsen, Ph.D., a co-author on the study and director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, explained the exciting applications that the Intestine-Chip opens up for patients:

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Clive Svendsen

“This pairing of biology and engineering allows us to re-create an intestinal lining that matches that of a patient with a specific intestinal disease—without performing invasive surgery to obtain a tissue sample,” he said in a press release. “We can produce an unlimited number of copies of this tissue and use them to evaluate potential therapies. This is an important advance in personalized medicine.”

Emulate’s sights are not just set on the human intestine but for the many other organs affected by disease. And because disease rarely impacts only one organ, a series of Organs-on-Chips for a particular patient could be examined together. Geraldine A. Hamilton, Ph.D., president and chief scientific officer of Emulate, Inc. summed up this point in a companion press release:

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Geraldine Hamilton

“By creating a personalized Patient-on-a-Chip, we can really begin to understand how diseases, medicines, chemicals and foods affect an individual’s health.”

 

 

Modeling Heart Disease: This Time on a Chip

Scientists at Harvard University have developed a new way to model congenital heart disease. Though researchers have previously generated heart cells derived from patients in a petri dish, this time scientists did so with groundbreaking ‘organ-on-a-chip’ technology—proving that this new type of technology can replicate a genetic disorder in the lab.

The research, which was published Sunday in Nature Medicine, describes how the Harvard team painstakingly grew human heart tissue that mimicked a type of congenital heart disease called Barth syndrome.

Barth syndrome, a type of congenital heart disease normally affecting boys, is caused by a single genetic change, or mutation, in the gene called TAZ. There is currently no way to treat or cure Barth syndrome. So in recent years scientists have looked toward regenerative medicine first to try and replicate the disease in a dish, with the ultimate goal of finding a way to fix it.

Though the team focused on Barth syndrome, these findings offer hope for any number of known genetic mutations that lead to congenital heart disease. It is estimated that 1 out of every 100 babies are born with some form of congenital heart defect—some of which can be fatal. But there is still much to learn, and as Dr. Kevin Kit Parker, one of the study’s lead authors stated in yesterday’s news release:

“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.”

The researchers started by taking skin cells from patients with Barth syndrome, manipulating the cell samples with the help of induced pluripotent stem cell (iPS cell) technology to transform them into embryonic-like stem cells. This would normally be the time where the researchers would attempt to grow heart muscle cells from these iPS cells in a petri dish. But here is where the Harvard team took a different approach.

Instead of growing these cells in a dish, the team instead grew them in a specially designed chip, lined with human proteins that mimicked the cells’ natural environment: the underlying architectural matrix of the heart. And when comparing cells derived from Barth syndrome patients with those of healthy people, the team noticed a clear difference. As Parker explained:

“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.”

Upon studying the newly generated tissue, the researchers were able to see for the first time an underlying metabolic mechanism that leads to the disease. They found that the TAZ mutation causes cells to produce an excess of something called reactive oxygen species, or ROS, a cellular byproduct equivalent to exhaust from the tailpipe of a car. A certain amount of ROS is normal, but too much can be a bad thing—harming essential cellular processes. But in the second part of the study, Dr. William Pu, the study’s other lead author, describes a potential solution:

“We showed that, at least in the laboratory, if you can quench the excessive ROS production then you can restore contractile function. Now, whether that can be achieved in an animal model or a patient is a different story, but if that could be done, it would suggest a new therapeutic angle.”

As Pu suggests, the team’s immediate next steps are to test their approach in animal models, while at the same time using the current ‘heart disease on-a-chip’ model to screen for small molecules that might help reduce excess ROS. And while it’s still early days, Parker is optimistic that this technology could speed the development of treatments for Barth syndrome and other congenital diseases:

“We tried to thread multiple needles at once and it certainly paid off. I feel that the technology that we’ve got arms industry and university-based researchers with the tools they need to go after this disease.”

How are CIRM-funded scientists using stem cell technology to fight heart disease?

Anne Holden