Growing a 3-D heart chamber in the lab

Stem-cell scientistshave grown a tiny beating human heart chamber in the laboratory. The little bundle of pulsating cells can be used to test new drugs – and is a step toward growing full-sized human hearts to replace diseased organs.

Kevin Healy and his team at the University of California have made the tiny hearts by reprogramming skin cells into functioning cardiac cells. They published their discovery in Nature Communicationsin July.

Melissa Little, a stem-cell biologist at Murdoch Childrens Research Centre in Melbourne, Australia, says the work is a “very big step forward”. “I think what we have now is a source of cells we can genuinely use.”

To take a single drug from the lab to the clinic costs pharmaceutical companies around $2.6 billion. The costs rise as the drug moves along the testing chain – from cells to animals to humans.

Developers have been looking for new ways to eliminate unsafe or ineffective drugs early in the process. They already test drugs on cells in the laboratory, but “the cells in your body don’t sit in a dish”, says Healy. A real organ is a dynamic, complex environment typically incorporating multiple cell types.

So researchers are trying to grow “organoids”– miniature 3-D organs – for the purpose of drug testing. Active cardiac cells tend to show up a drug’s side effects immediately, so there’s a big push to make mini-hearts.

Beating heart cells have already been grown in a single two-dimensional sheet in a dish but Healy’s group wanted to grow a three-dimensional heart chamber. To do so they used stem cells made from human skin cells and designed a well, about four human hair widths wide, for the cells to grow in. Stem cells added to the dish settled on the floor of the well, but started to move and stack up towards the edges. When the team added molecular cues known to promote heart tissue formation, the cells began to grow up the well walls and organise themselves into a small chamber with a hollow centre – around 500 times smaller than an adult heart chamber. By day 15, that chamber started beating.

Healy next tested whether the 3-D chamber would show a drug’s side effects. He added thalidomide, a morning sickness drug prescribed in the 1950s and ’60s that was later shown to cause profound birth defects. He found the thalidomide-treated chambers were much smaller and didn’t contract as strongly – in line with the effects seen in thalidomide babies, who were often born with a host of developmental cardiac problems including holes in their heart.

His team is already growing liver organoids to create a “multi-organ device” that connects artificial heart and liver organoids to each other with synthetic blood. Some drugs may not directly affect cardiac cells, Healy says, but the byproducts produced when the drugs are broken down by the liver could be damaging to the body.

Researchers have also built miniature brains, kidneys and stomachs. One day a whole body system, connected by synthetic blood, may be used to test drugs in the laboratory.

So does growing a microscopic heart chamber bring us any closer to growing full, transplant-worthy organs?

The heart beating in your chest is made up of cardiac cells supported by protein scaffolding called the extracellular matrix. In 2008, tissue engineer Doris Taylor’s group at the Texas Heart Institute was the first to drain a rat heart of all its cells, leaving the extracellular matrix behind. When her team seeded fresh cardiac cells into nooks in the scaffold, the cells could follow molecular signposts on the scaffold and resume their rightful places – and the heart started beating again.

Nadia Rosenthal, stem cell biologist at Monash University, speculates researchers may one day use 3-D printers to make these scaffolds for new human hearts.“We don’t have the perfect recipe yet”, Rosenthal says – that is, we don’t know what molecular signposts the cells need to read to find their place in the scaffold. But we’re on our way, she says: “By trial and error and a little intelligent engineering we might get there faster.”

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Self-organizing human cardiac microchambers mediated by geometric confinement rance. Credit: Zhen Ma et al (2015), Nature Communications