January 18, 2019

Cardiovascular disease is the primary cause of mortality worldwide, with a contributing factor being the challenge of heart tissue regeneration. After a typical heart attack, a significant number of cardiac muscle cells (cardiomyocytes) die. This cell death leads to a drastic decrease in heart function with no treatments to heal or repair the damage. But what if we lived in a world where damaged heart tissue  could be replaced with cell from a patient’s own cells? In the current era of rapid medical advancements and personalized medicine, a team of researchers from Stanford University and the Stanford Cardiovascular Institute took the first step towards  characterizing cells which could potentially be used to treat heart disease.

Stem cells that are generated directly from adult cells are called induced pluripotent stem cells (iPSCs), and are usually derived from skin or blood cells. More recently, researchers have developed a method to take iPSCs from patients and derive cardiomyocytes (hiPSC-CMs). hiPSC-CMs are being used to model patient-specific diseases and test drug responses. However, they are still not ideal for repairing a damaged heart. hiPSC-CMs are less mature than normal cardiomyocytes and so have different characteristics from their adult counterparts. In a recent publication in Nature Communication, lead author Jared Churko, PhD, Assistant Professor at University of Arizona and former Instructor within the Stanford Cardiovascular Institute,  and senior authors Joseph Wu, MD, PhD, Director of Stanford Cardiovascular Institute, and Nathan Salomonis, PhD, Assistant Professor of Biomedical Informatics at Cincinnati Children’s Hospital Medical Center understood that more information was needed to understand hiPSC-CMs at a single cell level.

DNA is the genetic code that determines characteristics that make you, you. It is the blueprint for making proteins, which are the basis of all tissues in the body, including the heart. The intermediate step between DNA and proteins is RNA. If DNA is the instruction manual for producing all the RNA needed by a cell, RNA is the edited version that contains only those parts of the manual relevant to the specific task. Genes are the part of DNA or RNA that gives specific instructions for how proteins are made. Their expression is time-, tissue-, or circumstance-dependent. In this paper, the authors looked at the RNA expression within over 10,000  cells over time to determine which genes were turned off or on, either at the single-cell level or at a population level. Using this kind of analysis, the authors identified subpopulations of hiPSC-CMs with distinct gene expression profiles containing specific factors regulating them. Combining all the data, they derived a model in which distinct cell populations are associated with specific regulators of gene expression that mediate cardiac maturation. This new and improved level of understanding allows future researchers to enrich for cardiomyocyte subtypes at different stages of maturity and functionality. These can then be used to better repair damaged heart tissue, provide a better model of patient-specific disease, and to better test personalized drug responses. Disease models that closely mimic the patient are essential for understanding cardiovascular disease and developing new therapeutics. Findings like these will usher in an era where heart tissue growth can be stimulated, allowing damaged hearts to be repaired and reducing mortality from cardiovascular disease.

Stanford Cardiovascular Institute co-authors include Priyanka Garg, Haodi Lee, Jaecheol Lee, Quinton Wessells, Wen-Yi Chen, and Arun Sharma. Other Stanford co-authors are Barbara Treutlein, Shih-Yu Chen, Gary Mantalas, Norma Neff, Garry Nolan, and Eric Jabart. Researchers from Cincinnati Children’s Hospital and Zephryus Biosciences, Inc also contributed to this manuscript. This work was funded by the Canadian Institute of Health (grant number 201210MFE-289547), NIH (grant numbers 1K99HL128906, HL126527, HL141371, HL130020, HL123968, and HL128170), and NIH Progenitor Cell Biology Consortium (grant number PCBC_JS_2013/3_03).