According to the World Health Organization (WHO), cardiovascular disease, specifically ischemic heart disease, is one of the leading causes of death worldwide. Cardiovascular diseases result in an estimated 17.9 million deaths each year. This is about 31% of all deaths worldwide (1). Medical researchers are continually working on ways to reduce those numbers, including the development of new technologies to combat premature deaths from cardiovascular diseases. This article will focus, in particular, on the value of induced pluripotent stem cells (iPSCs) in cardiac research.

What are induced pluripotent stem cells?

iPSCs are a type of pluripotent stem cell. These are master cells that can differentiate into any cell or tissue the body needs. They are generated directly from somatic cells through ectopic expression of various transcription factors, such as

• Oct4,
• Sox2,
• Klf4, and
• c-Myc (OSKM) (2)

They’ve become key tools to model biological processes, particularly in cell types that are difficult to access from living donors. Many research laboratories are working to enhance reprogramming efficiency by testing different cocktails of transcription factors.

IPSCs are important in some areas of medical research

iPSCs have become essential in a number of different research fields, including cardiac research.

They are a valuable and advantageous technologic development for two main reasons:

1. iPSCs can differentiate into any specific cells needed
2. They come from a human patient’s adult cells (2).

iPSCs vs. embryonic stem cells

Most people have heard of embryonic stem cells, which are one variation of pluripotent cells. Like iPSCs, they can be used to replace or restore tissues that have been damaged. 

The problem is that embryonic stem cells are only found in preimplantation stage embryos (3). Whereas iPSCs are adult cells that have been genetically modified to work like embryonic stem cells. Thus, the term, induced pluripotent stem cells.

The development of iPSCs was helpful because embryos are not needed. This reduces the controversy surrounding the creation and use of stem cells. Further, iPSCs from human donors are also more compatible with patients than animal iPSCs, making them even closer to their embryonic cousins.

The Japanese inventor of iPSCs, Professor Shinya Yamanaka earned a Nobel Prize in 2012 “for the discovery that mature cells can be reprogrammed to become pluripotent.” (4) The  Prize was awarded to Dr. Yamanaka because of the significant medical and research implications this technology holds.

What can iPSCs do? The answer is a lot

iPSCs hold a lot of promise for transplantation medicine. Further, they are highly useful in drug development and modeling of diseases. 

• Transplantation medicine

iPSCs may become important in transplantation medicine because the tissues developed from them are a nearly identical match to the cell donors. This can potentially reduce the chances of rejection by the immune system (5).

In the future, and with enough research, it is highly possible that researchers may be able to perfect the iPSC technology so that it can efficiently reprogram cells and repair damaged tissues throughout the body.

iPSCs forgo the need for embryos and can be made to match specific patients. This makes them extremely useful in both research and medicine.

Every individual with damaged or diseased tissues could have their own pluripotent stem cells created to replace or repair them. Of course, more research is needed before that becomes a reality. To date, the use of iPSCs in therapeutic transplants has been very limited.

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• Cardiac research

One of the most significant areas where iPSCs are currently being used is in cardiac research. With appropriate nutrients and inducers, iPSC can be programmed to differentiate into any cell type of the body, including cardiomyocyte. This heart-specific cell can then serve as a great model for therapeutic drug screening or assay development.

Another notable application of iPSCs in cardiac research is optical mapping technology. Optical mapping technology employs high-speed cameras and fluorescence microscopy to examines the etiology and therapy of cardiac arrhythmias in a patient-like environment. This is typically done by looking into electrical properties of multicellular cardiac preparations., e.g. action potential or calcium transient, at high spatiotemporal resolution (6).

Optical mapping technology can correctly record or acquire data from iPSCs. iPSCs are also useful in mimicking a patient’s cardiomyocytes with their specific behaviors, resulting in more reliable and quality data of cardiac diseases.

Why iPSCs are so useful in cardiac research?

iPSCs are vital tools in cardiac research for the following reasons:

• The ability for patient personalization
• Their successful use in drug therapies
• The capacity for modeling inheritable cardiac diseases (8).

iPSCs are patient-specific because they are 100% genetically identical with their donors. This genomic make-up allows researchers to study patients’ pathology further and develop therapeutic agents for treating their cardiac diseases.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), help researchers predict the cardiotoxicity of drugs like with widely used chemotherapy reagents (10). Predictions like this were close to impossible before iPSC technology entered the research game.

iPSC’s ability to model diseases

iPSCs really come into play with their ability to model diseases. Because iPSCs are genetic matches to their living donors, they are uniquely useful for the study of genetic cardiac diseases like monogenic disorders. iPSCs help researchers understand how disease genotypes at the genetic level manifest as phenotypes at the cellular level (5).

Long QT syndrome, a condition that affects the repolarization of a patient’s heart after a heartbeat, is a notable example of iPSC-based disease modeling (7). This syndrome has been successfully modeled using iPSCs and is an excellent model for other promising target diseases (7).

Long QT syndrome is not the only disease that has been modeled by iPSCs. Other cardiac diseases like Barth syndrome-associated cardiomyopathy and drug-induced kidney glomerular injuries have been modeled as well (8).

Key takeaways about iPSCS in cardiac research

• iPSCs can be used to create excellent models for cardiac research (e.g., cardiomyocytes) allowing researchers to learn more about the etiology of disorders and how to treat them.
• Because they come directly from living human donors, they are 100% genetically compatible with the donor.
• In many instances, iPSCs replace the need for embryonic stem cells, thus avoiding the controversy associated with the use of embryos for research.
   
• Many cardiac disorders are genetic, including arrhythmias, coronary artery disease, and cardiomyopathy (9). Researchers use iPSCs to test for cardiotoxicity of drugs to help combat the devastating effects of these inheritable cardiac diseases. The aim is to identify drugs that are most likely to work but have only minimal side effects.
• iPSCs can work well with optical mapping technology to pinpoint the exact indices of the heart that are diseased. This allows the creation of a personalized therapeutic strategy for the condition. iPSCs can also model the cardiac disorder a patient is suffering from so that researchers can learn more about the disease and ways to treat it.

The bottom line

The advent of iPSC technology has created a wealth of new opportunities and applications in cardiovascular research and treatments. In the near future, researchers hope that iPSC-derived therapies will be an option for thousands, if not millions of patients worldwide.

More from this author:  The Promising Future of Nanomedicine and Nanoparticles

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References:

1. Cardiovascular diseases (CVDs) Fact sheet. Available at: https://www.who.int/health-topics/cardiovascular-diseases/#tab=tab_1. Accessed May 4, 2020.
2. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
3. Regenerative Medicine. Department of Health and Human Services. August 2006. Chapter 1.
4. The Nobel Prize in Physiology or Medicine 2012. NobelPrize.org. Nobel Media AB 2020. Mon. 4 May 2020. https://www.nobelprize.org/prizes/medicine/2012/summary Accessed May 4, 2020
5. Huang, C., Liu, C., Ting, C. et al. Human iPSC banking: barriers and opportunities. J Biomed Sci 26, 87 (2019). 1186/s12929-019-0578-x
6. Attin M, Clusin WT. Basic concepts of optical mapping techniques in cardiac electrophysiology. Biol Res Nurs. 2009;11(2):195‐207. doi:10.1177/1099800409338516
7. Ilanit Itzhaki, Leonid Maizels, Irit Huber, Limor Zwi-Dantsis, Oren Caspi, Aaron Winterstern, Oren Feldman, Amira Gepstein, Gil Arbel, Haim Hammerman, Monther Boulos, Lior Gepstein. Modelling the long QT syndrome with induced pluripotent stem cells. Nature. 2011 Mar 10; 471(7337): 225–229. 2011 Jan 16. doi: 10.1038/nature09747
8. Low L. A. and Tagle D. A. (2017). Tissue chips – innovative tools for drug development and disease modeling. Lab. Chip 17, 3026-3036. 10.1039/C7LC00462A
9. Kathiresan S, Srivastava D. Genetics of human cardiovascular disease. Cell. 2012;148(6):1242‐1257. doi:10.1016/j.cell.2012.03.001
10. Kim JJ. Applications of iPSCs in Cancer Research. Biomark Insights. 2015;10(Suppl 1):125‐131. Published 2015 Jul 29. doi:10.4137/BMI.S20065