New heart model offers a path toward treating cardiac scarring

Cardiac fibrosis, a pathological condition in which cardiac tissue is scarred or thickened as a result of aging, injury, or disease, further exacerbates myocardial dysfunction by reducing the heart’s pumping capabilities. Currently, there are limited therapeutic resources to target and treat cardiac fibrosis. One challenge is that traditional 2D fibroblast models fail to reproduce the complexity of the human heart.

In a study recently published in Circulation Research, researchers at Stanford University, led by co-first authors Hao Zhang, MD, and Rihua Huang, MD, with senior author Joseph C. Wu, MD, PhD, developed a platform based on human induced pluripotent stem cell-derived cardiac organoids (iPSC-COs) to screen antifibrotic compounds that could reduce or slow down the buildup of scar tissue, improving the heart’s ability to pump effectively. These 3D iPSC-COs capture interactions between cardiomyocytes and cardiac fibroblasts, showing the changes that occur when scar tissue builds up and impairs the heart’s ability to function properly.

The investigators made the organoids using fibroblasts grown from stem cell lines that carry a fluorescent reporter, so those cells light up the moment they switch into scar-producing myofibroblasts. That let the team pick out compounds that dampened fibrotic activity in the organoids. The same organoids also showed whether a compound harmed heart cells, giving a read on effectiveness and safety in one platform.
 

The team used the platform to test several U.S. Food and Drug Administration (FDA)-approved cardiovascular drugs. Notably, LCZ696 (sacubitril/valsartan) showed a strong antifibrotic effect in the 3D organoids but not in traditional 2D fibroblast cultures, suggesting that interactions among different cardiac cells are important for understanding this drug's antifibrotic potential.

The researchers identified PT30, a chemical derivative of the antimalarial drug dihydroartemisinin, as a promising antifibrotic compound with no significant toxicity in the organoids at effective concentrations. In mice, orally dosed PT30 stayed in the bloodstream longer and reached higher levels than its parent compounds, artesunate and dihydroartemisinin — a profile better suited to the long-term oral dosing that chronic fibrosis would require. They then tested it in two mouse models of cardiac fibrosis. In both models, oral PT30 improved cardiac function and reduced scar tissue, even when treatment began after heart function had already declined.

These findings highlight the potential of 3D cardiac organoids as a tool for discovering and evaluating new treatments for cardiac fibrosis and also identify PT30 as a promising candidate for further development. The authors caution that PT30 will need more extensive dose-ranging, pharmacokinetic, and long-term toxicology studies before it could be tested in people.

Additional Stanford Cardiovascular Institute, Stanford Department of Medicine, and Stanford University investigators include Lu Ren, Wenjuan Zhu, Yuanyuan Dai, Wenqiang Liu, Mengjie Xie, Xiu Liu, Renke Tan, Xiaochun Yang, Xu Cao, Xuekun Wu, Christopher Caridi, and David Solow-Cordero. Other authors include Phung N. Thai (UCLA), Matthew A. Wu and Rabindra V. Shivnaraine (Greenstone Biosciences).