Induced pluripotent stem cell-derived cardiomyocyte in vitro models: tissue fabrication protocols, assessment methods, and quantitative maturation metrics for benchmarking progress

The advent of human induced pluripotent stem cells (hiPSCs) and techniques
to differentiate cardiomyocytes from them has opened a viable path to
creating in vitro models of normal and diseased hearts, accelerating more
predictive drug screening and therapeutic strategies for cardiac
pathologies. Currently, hiPSC-derived cardiomyocytes (hiPSC-CMs) are more
similar to fetal than adult cardiomyocytes, leading many in the field to
explore approaches to enhance cell and tissue maturation. There are over
2,000 studies utilizing hiPSC-CMs in models composed of various
combinations of cell and extracellular matrix components, using a plethora
of differentiation protocols, culture formats, and methods for quantifying
cardiomyocyte function. To assess the current state of this rapidly
growing area, we systematically analyzed 300 studies using hiPSC-CM models
for their selection of hiPSC lines, hiPSC-CM differentiation protocols,
types of in vitro models, maturation techniques, and metrics used
to assess cardiomyocyte functionality and maturity. Here, we provide the
data compiled from our analysis of these papers so others in the field can
utilize it to inform their research. Based on this analysis, we
highlight the diversity of, and current trends in, in vitro model designs
and highlight the most common and promising practices for functional
assessments. We further analyzed outputs spanning structural maturity,
contractile function, electrophysiology, and gene expression and noted
field-wide improvements over time. Finally, we observe that a persistent
lack of coordination amongst investigators is limiting the field’s ability
to benchmark and advance hiPSC-CM function against previous studies. We
discuss opportunities to collectively pursue the common goal of hiPSC-CM
model development, maturation, and assessment that we believe are critical
to driving the entire community forward in engineering mature cardiac
tissue.