Abstract
Ischemic heart disease remains one of the most prominent causes of mortalities worldwide with heart transplantation being the gold-standard treatment option. However, due to the major limitations associated with heart transplants, such as an inadequate supply and heart rejection, there remains a significant clinical need for a viable cardiac regenerative therapy to restore native myocardial function. Over the course of the previous several decades, researchers have made prominent advances in the field of cardiac regeneration with the creation of in vitro human pluripotent stem cell-derived cardiomyocyte tissue engineered constructs. However, these engineered constructs exhibit a functionally immature, disorganized, fetal-like phenotype that is not equivalent physiologically to native adult cardiac tissue. Due to this major limitation, many recent studies have investigated approaches to improve pluripotent stem cell-derived cardiomyocyte maturation to close this large functionality gap between engineered and native cardiac tissue. This review integrates the natural developmental mechanisms of cardiomyocyte structural and functional maturation. The variety of ways researchers have attempted to improve cardiomyocyte maturation in vitro by mimicking natural development, known as natural engineering, is readily discussed. The main focus of this review involves the synergistic role of electrical and mechanical stimulation, extracellular matrix interactions, and non-cardiomyocyte interactions in facilitating cardiomyocyte maturation. Overall, even with these current natural engineering approaches, pluripotent stem cell-derived cardiomyocytes within three-dimensional engineered heart tissue still remain mostly within the early to late fetal stages of cardiomyocyte maturity. Therefore, although the end goal is to achieve adult phenotypic maturity, more emphasis must be placed on elucidating how the in vivo fetal microenvironment drives cardiomyocyte maturation. This information can then be utilized to develop natural engineering approaches that can emulate this fetal microenvironment and thus make prominent progress in pluripotent stem cell-derived maturity toward a more clinically relevant model for cardiac regeneration.
Highlights
Cardiovascular disease has remained the most common cause of mortality for over a century
Several promising advances of cardiomyocyte maturation have been made through the utilization of in vitro mechanical stimulation, electrical stimulation, extracellular matrix interactions, and co-cultures with non-cardiomyocytes, which mimic the natural physiological environment of CMs in vivo, known as natural engineering (Figure 5)
Collagen/matrigel seeded with human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) compacted around an anchored sutures were electrically stimulated gradually from 0 to 3 Hz for 7 days, since 3 Hz is equivalent to the average human fetal heart rate of about 180 bpm, and tested 0–6 Hz for 7 days to determine the limits of the engineered heart tissue (EHT)
Summary
Cardiovascular disease has remained the most common cause of mortality for over a century. During the natural developmental program in vivo, mechanical stimuli, electrical stimuli, extracellular matrix interactions, and non-cardiomyocyte interactions synergistically combine in a spatiotemporal manner to effectively drive CM maturity from the immature early fetal CM stage to the functionally mature adult CM stage.
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