The promise of cell therapies is twofold. Firstly, the ability to regenerate from injuries that do not normally heal, such as severed nerves, or large loss of tissue mass. Secondly, the ability to restore more youthful function to aged tissues that suffer from a lack of replacement somatic cells due to the decline of stem cell activity. This decline is in part due to a loss of viable cells, and in part due to changes in the signaling environment or damage to stem cell niches that cause stem cells to become less active in response. Which of these processes is the dominant cause of loss of activity with age most likely differs from cell population to cell population.

As noted in the research materials below, there is considerable enthusiasm for the use of cell therapies to regenerate damage to the heart, particularly that occurring as a consequence of a heart attack. However, the heart is a highly structured organ with an electrical component to its activity, and regenerative strategies must avoid disruption of that structure and behavior. Do so and the heartbeat becomes irregular, or perhaps worse than that. This makes the heart a more challenging target than organs such as the kidney or liver, which are less stringent in their requirements for a very specific structure and balance of cell populations.

Heart regeneration using stem cells: Why irregular heartbeats occur after transplantation

Once a part of a heart tissue is injured due to restricted blood flow during a heart attack, treatment options are dire to fix the function of the heart to previous capacity. Stem cells are promising because they can be manipulated to generate healthy cells to replace diseased cells. No other cells hold this promise. There are a few issues to clear before stem cell treatments can be implemented clinically for heart regeneration and one major obstacle is to understand why irregular, abnormal heartbeats occur two to four weeks after induced pluripotent stem cell-derived heart muscle cells are transplanted to the heart. The heartbeat stabilizes on its own after 12 weeks but researchers set out to find out why the arrhythmia occurs.

It was thought that the arrhythmia occurs from the activity of the transplanted cells. Arrhythmia during a heart attacks is often noted as “re-entry” or when the electricity inside the heart goes haywire and loops around inside the heart. Two previous groups who studied arrhythmia in hearts of transplanted cells thought it was not caused by re-entry, but that it is the activity of the transplanted cells. Therefore, this team set out to find the cause through observing the properties of the various cells according to time points.

They created embryonic stem cell-derived cardiomyocyte cells and observed their electrical properties. There are two types of heart muscle cells made from induced pluripotent stem cells. “Working-type“, which like the name implies, contracts and relaxes to produce exertion. The other is called “nodal-like“, which acts like an electric pacemaker. After the twelfth week in vivo, the graft starts to grow, but immediately after transplantation it is very small. At the twelfth week the small graft has grown and consists mostly of working-type cells. The nodal-like cells has decreased significantly by then. The researchers believe that the arrhythmia decreases then, because the number of and activity of the nodal-like cells have decreased, causing extra electrical activity to decrease. So why does the population nodal-like cells decrease in vivo? Two weeks after transplantation, it was observed that nodal-like cells don’t multiply after transplantation, while the working-type cells increase significantly after transplantation. “Perhaps if doctors could remove the nodal-like cells before transplantation, arrhythmia would not occur during future transplantation of heart cell grafts.”

Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo

Accumulating evidence suggests that human pluripotent stem cell-derived cardiomyocytes can affect “heart regeneration”, replacing injured cardiac scar tissue with concomitant electrical integration. However, electrically coupled graft cardiomyocytes were found to innately induce transient post-transplant ventricular tachycardia in recent large animal model transplantation studies. We hypothesised that these phenomena were derived from alterations in the grafted cardiomyocyte characteristics.

In vitro experiments showed that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) contain nodal-like cardiomyocytes that spontaneously contract faster than working-type cardiomyocytes. When transplanted into athymic rat hearts, proliferative capacity was lower for nodal-like than working-type cardiomyocytes with grafted cardiomyocytes eventually comprising only relatively matured ventricular cardiomyocytes. RNA-sequencing of engrafted hESC-CMs confirmed the increased expression of matured ventricular cardiomyocyte-related genes, and simultaneous decreased expression of nodal cardiomyocyte-related genes. Temporal engraftment of electrical excitable nodal-like cardiomyocytes may thus explain the transient incidence of post-transplant ventricular tachycardia, although further large animal model studies will be required to control post-transplant arrhythmia.