Researchers have successfully derived human-induced pluripotent stem cells (hiPSCs) from patients with advanced heart failure (HF) and reprogrammed them to differentiate into cardiomyocytes that are able to integrate with existing heart tissue.
“This novel source for patient-specific heart cells may bring a unique value to the emerging field of cardiac regenerative medicine,” writes the research team in the European Heart Journal.
“Myocardial cell replacement therapies have emerged as novel therapeutic paradigms for myocardial repair but have been hampered by the paucity of sources for human cardiomyocytes, by the lack of direct evidence for functional integration between donor and host cells, and by the anticipated immune rejection associated with allogeneic cell transplantation,” the researchers say.
The team, led by Lior Gepstein, Technion–Israel Institute of Technology, Haifa, Israel, aimed to target these obstacles by establishing and coaxing the cardiomyocyte differentiation of hiPSCs from patients with ischemic cardiomyopathy.
Dermal fibroblasts were obtained from two male patients (aged 51 and 61 years) with advanced two HF. The fibroblasts were reprogrammed to generate HF-hiPSCs by retroviral delivery of three reprogramming factors: Oct4, Sox2, and Klf4.
Control hiPSC lines were generated by reprogramming foreskin fibroblasts from a healthy individual.
Gepstein and team report that the resulting HF-hiPSCs displayed adequate reprogramming properties and could be induced to differentiate into cardiomyocytes with the same efficiency as control hiPSCs.
Gene expression and immunostaining studies confirmed the cardiomyocyte phenotype of the differentiating HF-hiPSC cardiomyocytes.
The generated hiPSC-derived cardiomyocytes also functionally integrated with pre-existing cardiac tissue in vitro. They also engrafted, survived, and integrated structurally with the host myocardium following in vivo transplantation into rats.
“In this study we have shown for the first time that it’s possible to establish hiPSCs from heart failure patients—who represent the target patient population for future cell therapy strategies using these cells—and coax them to differentiate into heart muscle cells that can integrate with host cardiac tissue,” said Gepstein.
“We hope that hiPSC derived cardiomyocytes will not be rejected following transplantation into the same patients from which they were derived. Whether this will be the case or not is the focus of active investigation.”
However, Gepstein warns that there are a number of obstacles to overcome before it would be possible to use hiPSCs in humans. “One of the obstacles in dealing with this issue is that, at this stage, we can only transplant human cells into animal models and so we have to treat the animals with immunosuppressive drugs so the cells won’t be rejected.” He says it may take at least 5 to 10 years before clinical trials could start.
By Nikki Withers