Twitching heart muscle patches generated in the lab can be grafted on to guinea pigs’ diseased hearts and improve heart function. That is what a team of researchers from Norway, Germany, Scotland and the USA found. They report these results in the latest issue of Science Translational Medicine.
Zebra fish and a few amphibian species can do it, mammals and humans cannot: replace dead heart muscle cells with new ones. In human beings a scar is left in the heart muscle following a heart attack, whereby heart function usually permanently declines. That is why cardiologists dream of replacing dead tissue with artificial tissue.
Researchers from the German Centre for Cardiovascular Disease (DZHK) and the University Medical Centre Hamburg-Eppendorf in collaboration with researchers from the Cardiac Exercise Research Group (CERG) from the Norwegian University of Science and Technology (NTNU) have been able to achieve considerable success in this highly competitive area of research. They succeeded in transplanting human heart tissue generated in the lab to diseased guinea pigs’ hearts. The human heart muscle tissue that was sawn onto the guinea pig’s heart, integrated, and the animals’ heart function improved by up to 30 percent.
Reprogrammed somatic cells turn into heart cells
The lead author of the study, Dr. Florian Weinberger explains what distinguishes this approach from other similar approaches: “We use induced pluripotent stem cells (iPS cells), which are reprogrammed human somatic cells from which all kinds of tissue can be grown. In contrast, groups outside of Europe often work with embryonic stem cells. However, in Europe these are not allowed to be used for transplantation in humans”.
And there is yet another crucial difference. The researchers have grown three-dimensional strips from the heart cells in the lab that are sewn onto the heart like a patch, whereas other groups inject cell suspensions directly into the heart muscle. Describing the advantages and disadvantages of both approaches Weinberger says “The majority of injected cells are washed out of the heart or do not survive the injection. This is inefficient and can also be dangerous if individual cells have not yet fully developed into heart muscle cells and are therefore still pluripotent, or in other words are capable of becoming any cell in the human body. These pluripotent cells could reach the body and form tumours”. On the other hand, cell injection can be easily carried out via a catheter. With the patches, the researchers require significantly less of the expensive cells. Furthermore, cells in the patches are less prone to leeching minimizing the risk of side-effects.
The scientists also performed control tests with other tissue patches, for which they used matrix or endothelial cell patches only. By doing so, they wanted to rule out that stabilisation of the heart muscle using any tissue led to an increase in function. However, that was not the case and the heart function in guinea pigs did not improve. To rule out false positive results by subjective assessments, the researchers carried out their tests in a blinded fashion, meaning that they did not know themselves which animal had received the heart tissue and which had received other tissue.
Original and replacement cells beat (mostly) in time
When the heart is injured after a heart attack, some muscle cells of the heart die. This, in turn, triggers compensatory mechanisms that may work for a while in retaining the heart function. However, in the long term, this may lead to heart failure. The researchers wanted to see if they can change this decline in heart function after heart injury and possibly prevent heart failure using the twitching patches.
The twitching patches from the lab have their own rhythm and they achieve their full capacity only when beating in synchrony with the original heart. This so-called ‘electric coupling’ is therefore important for the suitability of the replacement tissue. “By using a specialized microscope, we found evidence that some of the implanted heart muscle patches were electrically coupled with the rest of the heart. This means that in order for the muscle patches to improve heart function, the patches had to behave like the “native” heart tissue and beat in synchrony with the “native” heart” said Dr. Tomas Stølen, a researcher from CERG and a collaborator of the study.
Further support for translation
There are still a few necessary steps that will need to be taken in order to be able to use this method for patients. For safety reasons, the researchers must closely examine whether and how many cells are washed out. Furthermore, they want to perform dosage studies to assess whether the number of cells can be reduced for the same effect. The timing of the therapy could also play a role. It is not yet known whether there are differences in outcome if the tissue is transplanted shortly after damage or when the damage to the heart is already chronic. And finally, the experiments must be repeated with larger animals, such as pigs, whose cardiovascular system is much more similar to humans.
Tomas Stølen, researcher at CERG
Original paper: Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells. Translational Medicine 02 Nov 2016: Vol. 8, Issue 363, pp. 363ra148