In a step toward one of stem cell science’s chief goals, UW-Madison researchers have grown functional human artery cells that helped lab mice survive heart attacks.
The development, from the lab of stem cell pioneer James Thomson, could help scientists create arteries to use in bypass surgeries for cardiovascular disease, the nation’s top killer. Several challenges remain, however, and studies in people are years away.
“This work provides valuable proof that we can eventually get a reliable source for functional arterial endothelial cells and make arteries that perform and behave like the real thing,” Thomson said in a statement.
The research, reported Monday in the journal Proceedings of the National Academy of Sciences, is part of a federally funded effort at UW-Madison to create artery “banks” for cardiovascular surgery from universally compatible donors.
In a related project, other UW-Madison researchers are testing three-dimensional “heart patches” of heart muscle cells, grown from stem cells, in pigs. The goal is to replace diseased or damaged heart tissue in humans.
Since Thomson became the first scientist to successfully grow human embryonic stem cells in a lab in 1998, researchers around the world have been coaxing the universal cells into various cell types — heart, pancreas, kidney, brain — to develop therapies and better understand diseases.
Today, many researchers use cells reprogrammed to their embryonic state from mature cells — known as induced pluri- potent stem, or iPS, cells — as the raw material. Thomson helped discover iPS cells in 2007.
Many labs can convert embryonic stem cells or iPS cells into specific cell types, but developing specialized cell lines that are pure, functional and robust has been a challenge.
Thomson and his team set out to find a recipe for growing artery cells that would really function like arteries.
The researchers used two new techniques: single-cell RNA sequencing to identify genes highly expressed in cells that initiate artery development, and CRISPR-Cas9 gene editing to evaluate the function of the genes.
They found that five small molecules and growth factors are needed to encourage iPS cells to become functional artery cells. To their surprise, they discovered that insulin, a common growth factor that had been used before in trying to grow artery cells, actually inhibits such growth.
They used their recipe to make artery cells, and tested the cells in mice that had their left coronary arteries tied off to mimic heart attacks. Four weeks later, 83 percent of mice treated with the cells were alive, compared to 33 percent of mice that didn’t get the cells.
“We can use those cells to further create tissue-engineered arteries for bypass surgeries,” said Jue Zhang, a scientist in Thomson’s lab at the Morgridge Institute for Research and lead author of the study.
Developing off-the-shelf bypasses for surgery is the goal of an $8 million, seven-year grant UW-Madison received last year from the National Heart, Lung and Blood Institute to create universal artery “banks.”
The blood vessels of many cardiovascular disease patients aren’t suitable for use as bypasses, doctors say, and growing bypasses from individual patients’ stem cells would be timely and expensive. The hope is to use iPS cells from a rare population of genetically compatible donors to grow arteries anyone could use.
UW-Madison scientists, including engineers Tom Turng and Naomi Chesler and pathologist Igor Slukvin at the Wisconsin National Primate Research Center, plan to grow artery cells on scaffolds and test them in monkeys. If successful, the cells would be produced for human studies at the Waisman Biomanufacturing facility on campus.
The “heart patches” involve another $8.6 million, seven-year National Institutes of Health grant, shared with the University of Alabama-Birmingham and Duke University.
The patches involve three types of heart cells, derived from iPS cells, said Dr. Tim Kamp, a UW-Madison cardiologist and co-director of the university’s Stem Cell and Regenerative Medicine Center.
In studies in pigs, getting the patches to connect and survive when transplanted to pig hearts after heart attacks “remains a challenge,” Kamp said. Immune tolerance of the human grafts in pigs is another concern, he said.
But if such hurdles can be overcome, tests in humans could follow.