Advances Made in the Generation of Functional Arteries from Stem Cells

Advances Made in the Generation of Functional Arteries from Stem Cells

A team of researchers at the Morgridge Institute for Research in Madison, WI are using induced pluripotent stem cells (IPSCs) to create functional arteries that can be used to treat patients with cardiovascular disease.

The research team, led by James Thomson, first identified the pathways involved in the regulation of differentiation of arterial endothelial cells – The cells that line the inside of arteries and are in direct contact with blood. By manipulating those pathways, the researchers were able to generate functional arterial cells. The latest research centered on generating smooth muscle cells from IPSCs. Smooth muscle cells are the cells on the outside of arteries.

One of the problems encountered when generating smooth muscle cells from stem cells is the growth factors that are most commonly used can result in abnormal thickening – intimal hyperplasia – which can lead to narrowing of blood vessels. To generate functional arteries in the lab that can be transplanted into patients, this naturally needs to be avoided.

When intimal hyperplasia develops, smooth muscle cells undergo a process called contractile to synthetic phenotypic switching, where contractile protein expression decreases and proliferation, migration, and ECM matrix production increases.

To avoid the problem, the researchers used high throughput screening to identify drugs that inhibited intimal hyperplasia by promoting differentiation of contractile smooth muscle cells rather than synthetic smooth muscle cells.

Out of the 4,804 drugs tested, one stood out: RepSox. RepSox inhibited intimal hyperplasia in a rat balloon injury model and induced smooth muscle cells to exhibit a more contractile phenotype.

While their research was a success, the team is still some way off developing fully functional arteries that can be transplanted into patients. The latest study has produced a cell type that is better than previous attempts, but the researchers still need to mature the cells to make them more functional and more closely matched to native arteries.

Patients with occlusive arterial disease are often treated using balloon angioplasty, stents, or bypass surgery, but in many patients, restenosis – abnormal narrowing of the arteries – occurs as a result of intimal hyperplasia following surgery. The researchers suggest that RepSox could be used to treat patients following surgery to prevent restenosis. Further, RepSox has fewer side effects than the FDA approved drugs currently used to treat restenosis.

The research is detailed in the paper – A Human Pluripotent Stem Cell-Based Screen for Smooth Muscle Cell Differentiation and Maturation Identifies Inhibitors of Intimal Hyperplasia – which was recently published in Stem Cell Reports.  DOI: 10.1016/j.stemcr.2019.04.013

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