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Image by Piron Guillaume

Article by Jaron Whitehead & Roberta Lock

Filling The Hole in Your Heart 

Source Publication: 

Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Undergo Clonal Expansion In Vivo, Circulation, 2021

Danny El-Nachef, Darrian Bugg, and Kevin M. Beussman et al., Jennifer Davis Lab

Health monitoring devices include a wide array of technologies that provide patients and health care workers with vital information that can warn of life-threatening illness early. In an ideal device, extensive amounts of internal body system data should be obtainable with minimal patient discomfort and maximum ease of access. Unfortunately, this ideal still does not exist as most inclusive analysis can only be conducted with invasive techniques performed within a clinic, and non-invasive methods of data collection aren’t comprehensive. In this paper, researchers have developed a non-invasive method of monitoring two simple biomarkers present within the interstitial fluid via a wearable, skin adhering device that connects to a smartphone!

What did these researchers do?

In this study, researchers turned human pluripotent stem cells (hPSC) into cardiomyocytes (CM) to test their ability to grow onto a damaged heart. They used hPSC-derived CMs because the cells generated are genetically human and the number of CMs that can be generated is virtually limitless. This makes them attractive compared to other options for sourcing CMs for this purpose, like taking CMs from either animal or human hearts, which are very limited in number and have the potential for ethical complications. The CMs were labeled in different colors, and researchers monitored the CM growth and activity over 28 days in a lab setting. This labeling allows for the tracking of individual cells. This led to identifying what is happening to specific cells in the transplanted graft. Understanding this will help determine what cells are most effective in healing damaged myocardium (muscular heart tissue).

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 Reporter stem cell- derived cardiomyocytes 6 weeks after engraftment in the heart by J. Davis Lab


Why is this important?

The original method of heart grafts was inefficient at repopulating the myocardium (muscular heart tissue) and resulted in increased organ size without an increase in function. Why this disparity was occurring wasn’t understood, as once cells are transplanted, the activity of individual cells couldn’t be followed. Initially, the viability of cells within the graft was monitored through measurements of cell cycle activity (which measures cell division). However, this assessment fails to recognize complete CM division versus incomplete division. By labeling the grafted cells using different colors, activity of individual cells can be tracked, and whether they undergo complete or incomplete division can be determined. Increased understanding of what occurs following transplant will ideally lead to creating better grafts with cells that act a certain way once transplanted, which will then result in the overarching goal of increased heart function.  

How did the researchers do this?

These researchers genetically engineered hPSC-CM to display specific colors to illustrate best the cardiomyocytes that proliferate. This labeling system means that when an individual cell divides, the resulting cell will be the same color as the original cell. As a result, scientists could identify the specific CMs that divide, how long they divide for, and analyze their functional properties. First, they noted which cardiomyocytes proliferated in vitro (in a dish) and conducted further tests on them. One of the tests conducted was RNA sequencing to study their gene expression to see what genes make CMs divide more frequently. Then, to see if this proliferation still occurred in in vivo (in a living being) settings, labeled CMs were grafted into a rat. Interestingly, when they finally removed the graft at the end of the experiment, they found heterogeneous proliferation levels, meaning that the graft areas had different colors and numbers of CMs of each color. Thus, in vivo, some CMs divided continuously, but the cells that divided were in different spots in the graft and not evenly placed.

What comes next?

The work presented in this study shows promise in increasing our understanding of how hPSC-derived CMs act in a graft for the purpose of sealing heart punctures. There are several next steps to take in this line of research to optimize this type of graft. They’ve determined that there is a subset of CMs with the ability to divide, which would be optimal for sealing tears in the myocardium. However, there is currently no way to separate those cells from cells that do not proliferate. Additionally, it isn’t known if the dividing cells will stop proliferating once the gap is filled. Ideally, this process of cell division could be controlled to stop cell division once the heart heals completely. Finally, this graft was only tested in one area of the heart. How would the graft perform in different areas? The ventricles of the heart are different from the atria, and thus might have different requirements for the cells being grafted. Eventually, this would also have to be tested in larger animal models.

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