Abstract
Heart diseases remain a major cause of mortality and morbidity worldwide. However, terminally differentiated human adult cardiomyocytes (CMs) possess a very limited innate ability to regenerate. Directed differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into CMs has enabled clinicians and researchers to pursue the novel therapeutic paradigm of cell-based cardiac regeneration. In addition to tissue engineering and transplantation studies, the need for functional CMs has also prompted researchers to explore molecular pathways and develop strategies to improve the quality, purity and quantity of hESC-derived and iPSC-derived CMs. In this review, we describe various approaches in directed CM differentiation and driven maturation, and discuss potential limitations associated with hESCs and iPSCs, with an emphasis on the role of epigenetic regulation and chromatin remodeling, in the context of the potential and challenges of using hESC-CMs and iPSC-CMs for drug discovery and toxicity screening, disease modeling, and clinical applications.
Highlights
Human embryonic stem cells, isolated from the inner cell mass of blastocysts, have the ability to propagate indefinitely in culture and can differentiate into any cell type in the body
Using a series of defined growth factors to guide differentiation toward the cardiac lineage, directed differentiation protocols that significantly enhance the generation of Human embryonic stem cell (hESC)-derived and Human induced pluripotent stem cell (hiPSC)-derived CMs have been developed [34,35,36,37]
The use of growth factors, chemically synthesized molecules, epigenetic modifiers, miRNAs, or cardiac-specific transcription factors has significantly improved the yield of cardiac differentiation to close to 100%
Summary
Human embryonic stem cells (hESCs), isolated from the inner cell mass of blastocysts, have the ability to propagate indefinitely in culture and can differentiate into any cell type in the body. Using a series of defined growth factors to guide differentiation toward the cardiac lineage, directed differentiation protocols that significantly enhance the generation of hESC-derived and hiPSC-derived CMs have been developed [34,35,36,37]. Sequential addition of activin A and BMP4 to defined RPMI/B27 medium together with double layers of a commercially available extracellular matrix (Matrigel) on day −2 and day 0 of differentiation provided a favorable microenvironment that further promotes epithelial– mesenchymal transition for precardiac mesoderm formation Such a matrix sandwich method results in the efficient production of CMs from multiple hESC and hiPSC lines with high yields and a purity of up to 98% cTnT+-derived cells [37].
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