By Lilly Su, MD Candidate, Class of 2023, Penn State College of Medicine.
Previously, we discussed the different types of stem cells. Human-induced pluripotent stem cells (hiPSCs) are cells with very similar characteristics to embryonic stem cells, as both types of cells are able to self-renew and differentiate into other types of cells. In this article, we focus specifically on the use of hiPSCs in congenital heart diseases and how they have been helpful in understanding the genetic aspects of various heart diseases.
The major causes of mortality and morbidity are cardiovascular disease and heart failure. Whether it is due to chemotherapy-derived cardiotoxicity, congenital defects, or myocardial infarction, there is irreversible damage done to the heart. This is due to the nature of cardiomyocytes, as they have very limited ability to withstand injury and aging, and cardiomyocytes cannot renew. With the lack of ability for cells to regenerate and renew, the only other option to replace these damaged cells is to completely replace them with functional cardiomyocytes through transplantation.
Studies have shown that while environmental factors, such as intrauterine environment, maternal conditions, and exposures, can contribute to congenital heart disease (CHD), genetic factors are the predominant cause. Having a better understanding of the underlying genetics of CHD allows researchers to accurately diagnose patients who have these diseases and the development of cell culture and animal models that can be used to better understand disease pathophysiology and mechanism. However, since there are limited animal models available to study the genetics of CHD, this is where hiPSCs come in. Derived from somatic cells, hiPSCs have the potential to become any cell type in the body and compared to animal models, patient hiPSCs already contain the genetic background of the affected individual with the disease of interest. These patient hiPSCs that have the ability to differentiate into a variety of caradiac cells – cardiac fibroblasts, smooth muscle cells, cardiomyocytes, etc – provide the ideal environment to study how genetics can contribute to the development of CHD.
There are two categories that the genetic basis of CHD can be categorized into: syndromic CHD and non-syndromic CHD. Syndromic CHD is when there are other congenital anomalies or neurodevelopmental defects in addition to the CHD, whereas non-syndromic CHD is when the CHD is isolated. Some examples of syndromic CHD include Down syndrome (trisomy 21), Turner syndrome, and Alagille syndrome. A chromosomal anomaly, Down syndrome patients can present with various types of CHD, such as atrioventricular septal defect, ventricular septal defects, secundum atrial septal defects, and patent ductus arteriosus. On the other hand, Turner syndrome is caused by either a complete or partial loss of an X-chromosome, and presents with bicuspid aortic valves, aortic coarctations, or septal defects.
Because patient-derived iPSCs can be used to model a variety of CHD (cardiac septal defects, aortic stenosis, calcific aortic valve disease), they are promising tools to use to study the genetic mechanisms of isolated CHD that are caused by single-gene defects. Whether it is studying the patient-derived cardiac cells carrying genetic variants in a petri dish to better understand the disease mechanism, or in conjunction with transgenic mouse models and clinical genetics, human iPSCs have been fundamental in further unlocking the role of genetics in CHD pathophysiology.
References
- https://www.nature.com/articles/ng.3870
- https://www.frontiersin.org/articles/10.3389/fcell.2021.630069/full
- https://pediatricheartspecialists.com/heart-education/blog/55-down-syndrome-and-congenital-heart-disease