Blood banks have been vital in medical care since the early 1900s, and now a team of scientists at the Morgridge Institute for Research in Madison, Wisconsin, wants to take the concept a step further. They're using stem cells to build new arteries for patients with cardiovascular diseases. And along the way, they identified a drug that could help reduce complications in patients undergoing bypass surgery.
Regenerative biologist James Thomson led a team that used pluripotent stem cells to grow smooth muscle cells, one of the two cellular building blocks of functional arteries, according to a study published in the journal Stem Cell Reports.
With help from a small-molecule drug called RepSox, the researchers perfected the building process, they said. The same compound may also lower the risk of a potentially dangerous complication that’s commonly seen in patients who have corrective surgeries such as balloon angioplasty, stents and bypass surgery for their arterial disease.
The Thomson lab at Morgridge previously used single-cell RNA sequencing and CRISPR-Cas9 to identify pathways that regulate differentiation of arterial endothelial cells—a pillar of arteries. After manipulating the pathways, they successfully generated functional arterial cells. This time, they focused on smooth muscle cells.
Widely used growth factors for producing smooth muscle cells from stem cells can also cause an abnormal thickening called intimal hyperplasia, the study’s first author Jue Zhang explained in a statement. Intimal hyperplasia can cause narrowing of the blood vessels, a phenomenon known as restenosis. “It’s a common problem in smooth muscle cell differentiation, and if you want to make a useful artery, you don't want that risk,” he said.
To restore the contractile ability of smooth muscle cells and thereby facilitate better blood flow, the team used high-throughput screening to identify small molecules that can overcome the problem. RepSox stood out among 4,804 drugs. In contrast to commonly used growth factors, RepSox inhibited intimal hyperplasia in a rat balloon injury model, and it’s more stable and less expensive, the researchers reported.
They believe RepSox could also serve as a drug to treat restenosis in patients post-surgery. “Currently there are only two FDA-approved drugs on the market [to address these problems], and they're not cell-type specific, meaning they have side effects,” Zhang said. “We found that RepSox inhibits intimal hyperplasia and has fewer side effects.”
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Damages to the cardiac system are difficult to repair, but scientists are examining different regenerative methods. A team at Stanford University recently found that a protein called CXCL12 could help grow collateral arteries when the heart’s major arteries are blocked. The Hippo signaling pathway, known to control organ size and cell death, was previously found to prevent damaged heart muscle from repairing itself. When scientists at Baylor College of Medicine silenced it, they restored the heart’s pumping ability in mouse models of heart failure.
Researchers in Israel even successfully printed a small 3D human heart using bioinks developed from a patient’s own cells.
While the current study brings the Morgridge team closer to the goal of building arteries, there’s still work to be done. “Basically this cell type is better than previous efforts, but it's still not mature yet,” Zhang said. “We need to induce these cells to become more mature, to be more similar to our native artery, to make it more functional.”