Delivering cardiac organoids to help the heart to recover after a heart attack

Making research breakthroughs in the laboratory relevant to clinical care requires close collaboration between basic scientists and clinician-researchers.

That’s why bioengineer Ying Mei, Ph.D., who has a joint appointment at Clemson University (CU) and MUSC and is part of the CU-MUSC program in Bioengineering, turned to MUSC Health vascular surgeon Jean Marie Ruddy, M.D., for clinical insights on how and when the cardiac organoids he develops could be used clinically to restore tissue after a heart attack.

“I think that collaboration is extremely important because I’m a basic scientist coming up with a ‘crazy’ idea, which might look beautiful in a publication but turn out not to be as clinically meaningful,” said Mei. “I need a vascular surgeon collaborator to tell me which kinds of procedures are clinically feasible.”

“Without enough oxygen, there is a lot of cell death, and the heart loses its ability to pump and push blood to the rest of the heart and body. That’s why I am interested in how cardiac organoids could assist with the recovery of heart tissue after a heart attack.”

-- Dr. Ying Mei

Ruddy envisioned a precise clinical scenario for the administration of the cardiac organoids: They could be delivered to damaged vessels as blood flow was being restored in the cardiac catheterization lab after a heart attack.

“The first step to translating a research breakthrough is demonstrating that we have a very particular patient scenario where it will be relevant and a model with which we can replicate it, and we have both,” said Ruddy.

With discovery pilot funding from the South Carolina Clinical & Translational Research (SCTR) Institute, Mei and Ruddy will test their idea that cardiac organoids could be used to improve heart tissue recovery after a heart attack in a preclinical model that simulates the clinical scenario in the cath lab.

“This seed grant is extremely important in the sense that it allows us to test high-risk, high-reward ideas,” said Mei. “Without seed grants, it’s hard to obtain the preliminary data you need to be funded when you have a crazy idea that could be clinically meaningful.”

Why is this research important?

Heart disease, which can culminate in a heart attack, is the No. 1 killer in the U.S. and the world. During a heart attack, the major arteries that feed the heart oxygen become blocked.

“Without enough oxygen, there is a lot of cell death, and the heart loses its ability to pump and push blood to the rest of the heart and body,” said Mei. “That’s why I am interested in how cardiac organoids could assist with the recovery of heart tissue after a heart attack.”

The crazy idea

Cardiac organoids, which are like mini-hearts in a dish, are three-dimensional microtissues made up of stem cell-derived heart muscle cells and other supportive cell types that the heart tissue needs.

“The first step to translating a research breakthrough is demonstrating that we have a very particular patient scenario where it will be relevant and a model with which we can replicate it, and we have both.”

-- Dr. Jean Marie Ruddy

Stem cells can be made into any cell type depending on the conditions in which they are grown. Cardiac organoids specifically use stem cells that can self-renew and generate heart muscle cells. These cardiac organoids also contain other supportive cell types that are found in the heart to promote stability and integration into the heart tissue.

In a preclinical model, Mei and Ruddy will study whether cardiac organoids can be used to fix heart damage by targeting them to the area where the heart cells died during a heart attack.

In previous studies, researchers have seen some improvement using stem cell-derived heart muscle cells to treat damage after heart attacks. In those studies, the heart muscle cells were injected into the heart but were quickly pushed out into the circulatory system where they were free to go anywhere else in the body. Since the heart works like a pump, it squeezes the muscle cells out of the heart, leaving only a small subset behind.

Mei and Ruddy are hoping that the cardiac organoids will prove “stickier” than the stem cells alone and remain in the heart where they can promote tissue recovery.

In their preclinical model, Mei and Ruddy will interrupt blood flow, simulating the lack of oxygen received during a heart attack, and then restore the flow using a method seen in the cath lab. While blood flow is being restored, cardiac organoids will be delivered to the damaged area of the heart muscle via blood vessels. Often the blood vessels are also damaged, so delivering cardiac organoids through this method could also repair damage to the blood vessels.

The cardiac organoids would also be injected directly into the heart muscle, an existing delivery mechanism for stem cells. Mei and Ruddy will then be able to determine if the new delivery method is more effective and allows the cardiac organoids to stick and not be pushed out of the heart.

“We will try introducing them in the coronary vasculature directly in the region where we've interrupted flow to see if we can improve delivery and if that will facilitate those cells taking hold and helping the heart muscle to recover after the injury,” said Ruddy.

If this “crazy idea” proves successful, it would be a potential early interventional method for treating heart damage during heart attacks in a clinical setting.