Three advances in stem-cell-derived cardiac models and therapies

BioTechniques News
Aisha Al-Janabi

Aisha Al-Janabi, our Assistant Editor, explores recent cardiovascular disease research, which includes developing heart organoids with vascular cells, launching cardiac chips to the International Space Station (ISS) and using stem-cell therapy to repair damaged heart muscle.

Introducing vascular cells into cardiac organoids

Organoids are 3D cellular complexes generated from human-derived adult stem cells that self-organize into tissue models with high parity to their in vivo counterparts due to the developmental biological signals provided by their environment. These models provide an accurate platform for testing drugs in vitro and studying disease mechanisms. Organoids of the heart can be used to improve understanding of cardiovascular disease, the leading cause of death in Australia. [1, 2]

Previously, scientists were not able to incorporate vascular endothelial cells into cardiac organoids, which are cells that act as a protective barrier lining arteries, veins and capillaries. Now, a collaboration of teams across Australia, led by the QIMR Berghofer Medical Research Institute (Brisbane, Australia), has successfully added these cells into cardiac organoids, introducing a vascular system for the first time.

“Each organoid is only about the size of a chia seed, measuring just 1.5 mm across, but inside are 50,000 cells representing the different cell types that make up the heart,” explained James Hudson (QIMR Berghofer Medical Research Institute), senior author of the paper.

The researchers found that the addition of vascular endothelial cells enhanced the organoids’ maturation, improving their function. This resulted in a stronger heartbeat and indicates the importance of the vascular system in organoid models.

Utilizing their heart model, the research team focussed on identifying therapeutics to repair different types of heart damage including damage caused by inflammation. Inflammation makes the heart stiffen so it cannot fill with enough blood.

“When we stimulated inflammation in our mini heart muscles, we found the vascular cells played a central role. We only saw the stiffening in the tissues that had the vascular cells,” explained Hudson. They found that, when inflamed, heart cells released endothelin, which is a factor that mediates stiffening and regulates blood pressure. Targeting this mechanism could lead to novel therapeutics for inflammation-driven cardiac dysfunction.

Hudson commented, “We only know a fraction about the biology underpinning the heart so we’re constantly trying to improve our cardiac organoids to simulate the heart’s complex cellular interactions and tissue composition.”

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Launching cardiac tissue chips into space

Exposure to microgravity for a prolonged period of time weakens heart muscle and engineered heart tissue quicker than on Earth, giving researchers the opportunity to study the progression of heart disease at an expedited rate. To take advantage of this, tissue chips were launched into space on the 15th of March 2023 in NASA’s Commercial Resupply Service Mission to the ISS called SpaceX CRS-27, or SpX-27. [3]

This is part of the Tissue Chips in Space initiative, a collaboration between the National Institutes of Health’s National Center for Advancing Translational Science (MD, USA) and the ISS National Lab (Space). Organs-on-a-chip are microfluidic cell cultures that are manufactured to model the structure and function of organs, which can also be used to screen drugs and monitor cell functions.

Cardinal Heart 2.0 is one of the experiments being carried to the ISS, sending more than 3,000 beating cardiac chips to space. The research team led by Joseph Wu (Stanford University, CA, USA) will use these chips to assess if engineered heart muscle tissue grown in microgravity could be used as a model for heart failure.

“We know that prolonged stress environments like microgravity can cause weakening of cardiac muscle cells, producing symptoms that we see in patients that suffer from heart failure on Earth,” said Dilip Thomas, a researcher at Stanford University who is part of the Cardinal 2.0 team. “We can use the ISS to model a lot of the diseases that we see in patients on Earth but on an accelerated timeline.” [4]

Prior to take-off, the researchers treated the engineered cardiac tissue chips with existing FDA-approved drugs to assess which therapeutics reduce the effects of microgravity on the tissue. Testing existing drugs will allow the researchers to analyze if the tissue chips are an effective model for heart disease.

They will also study the effects of space flight on cardiac tissue by sending one group of samples that are chemically fixed at a defined time point and another group that will be returning live, to investigate the effects of space launch and landing.

Another project in the Tissue Chips in Space program is led by a team of researchers from Johns Hopkins University (MD, USA). They will be monitoring the contractile forces of the cardiac tissue chips in real time to understand how cardiovascular diseases progress over time. [5]

“We are going to examine the rate at which these cardiac tissues beat over the period of one month and compare that to ground-based experiments to test out the effectiveness of new therapeutics,” commented Deok-Ho Kim, a Professor of Biomedical Engineering.

Additionally, the researchers will be investigating how to preserve cardiac function in microgravity by administering a variety of therapeutics on 24 tissue chips containing cardiac cells differentiated from human-induced pluripotent stem cells. They hope the findings from their experiments in space will lead to improved treatment options on Earth for heart disease, as well as an understanding of how space travel impacts astronauts’ health.

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Engineered stem cells repair damaged heart muscle

Research is ongoing as to how human pluripotent stem cells could be used to treat damaged heart muscle, tissue that does not naturally regenerate after it is damaged and is instead replaced with scar tissue, which can lead to heart failure.

A research group at the University of Washington School of Medicine in Seattle (WA, USA) led by Chuck Murry used pluripotent stem cells to generate cardiomyocytes to repair damage following myocardial infarction – a type of heart attack caused by blocked blood flow to the heart. [6, 7]

In previous animal studies, the research group injected the stem cells into heart walls. These successfully created new muscle cells that integrated with the existing heart muscle and beat in synchrony; however, during the early weeks of engraftment, the heart would beat at a dangerously high rate making this treatment unsafe. To overcome this, “our goal is to create working contractile cells that would not try to set their own pace,” commented Murry.

In mature hearts, specialized pacemaker cells generate electric signals at regular intervals to induce the other heart cells to contract at a suitable heart rate. However, in embryonic hearts, all heart cells act as pacemakers with few quiescent contractile cells. The research team hypothesized that their engrafted stem cells were chaotically generating signals because they were behaving like embryonic cells, leading to the dangerous heart rate and arrhythmia observed.

To test their theory, the researchers used RNA-sequencing and CRISPR-based genome editing knockout experiments to identify the ion channels behind the irregular heartbeat.

Using the results, they created a stem cell line that produced cardiomyocytes that are electrically quiescent and contract according to an electrical signal. They called these MEDUSA cells (Modifying Electrophysical DNA to Understand and Suppress Arrhythmias). When engrafted into hearts, the MEDUSA cardiomyocytes matured into adult cells and beat in synchrony with the natural pacemakers, which did not give rise to a dangerously high heart rate.

Additional testing of these engineered stem cells is still required but Murry hopefully added, “I think we’ve overcome the biggest roadblock to regenerating the human heart.”

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