NEW YORK (Reuters Health) – Human engineered heart tissue (EHT) patches to help remuscularize an injured heart can now be made large enough for clinical use, new research shows.
“We believe that the study is an important step towards cardiac repair with stem cell-derived heart-muscle patches,” said Dr. Thomas Eschenhagen of University Medical Center Hamburg-Eppendorf, in Hamburg, Germany.
“We have now a clearer picture of the minimal dose and have established a method to generate human-scale patches that are stable and large enough to be easily transplanted onto the injured human heart,” he told Reuters Health by email.
Dr. Eschenhagen and colleagues note that although human EHT transplantation has shown success in preclinical models, scaling the transplant to a clinically relevant size and meeting good manufacturing practices (GMP) have been challenging.
The researchers differentiated cardiomyocytes from three different human induced pluripotent stem cell lines including one reprogrammed under GMP conditions. Aspects of culture arrangements for the latter were adapted to contain only GMP-grade reagents.
In a dose-finding study, cryo-injury of the left ventricular wall was induced in female guinea pigs. After seven days, EHT patches with a mesh structure and different cell densities were then sutured above the scar. Cyclosporine was used for immunosuppression.
The team found dose-dependent remuscularization, with only high-dose patches improving left-ventricular function. Compared with cell-free patches, those with lower cell numbers did not improve function.
The team also established that cardiomyocyte proliferation after transplantation played a role in graft development. These results, they say, “indicate that the final graft size depends not purely on cell survival, but additionally on proliferation.”
The researchers then went on to use human-sized patches (5 x 7cm) in pigs that were pharmacologically immunosuppressed with a variety of agents. “Human scale patches,” they observe, “resisted the mechanical forces of the pig heart and patch transplantation was technically easy, demonstrating the surgical feasibility of this approach.”
But, they add, “Standard pharmacological immunosuppression resulted in only very low cell survival.”
Although progress has been made, Dr. Eschenhagen concluded that the study “also shows the problems of immune reaction in pigs. This made us enter into a partnership with Evotec AG to develop hypoimmunogenic heart muscle patches that will spare patients from long-term high-dose immune suppression therapy, one of the risks of transplanting allogeneic (foreign) stem cell-derived cells. We hope that first clinical applications will start in 3 years.”
Dr. Eschenhagen and other authors are co-founders of EHT Technologies GmbH. A patent has been filed describing the generation of human-scale EHT patches.
SOURCE: https://bit.ly/30Ps5zU Circulation, online March 2, 2021.