Abstract
Human cell lines, including disease cell lines are often superior to routine animal models for the purposes of rapid and safe assessment of the effects of different agents that may modulate myocardial functioning under physiological and pathological conditions. There are several currently existing methodologies for derivation of cardiomyocyte-like cells by targeted differentiation from pluripotent cells and by reprogramming/transdifferentiation from other types of cells (multipotent progenitors, somatic cells, etc). The present paper reviews the potential sources of cells capable of differentiation along the cardiomyocyte lineage; the existing methodologies for targeted differentiation, outlining the specificities of each method; and the markers for differentiation along the mesodermal and the cardiogenic lineage. The yield of robustly beating cells expressing cardio-specific proteins derived by any of the existing methods, however, still rarely exceeds 70-90 %, even with the newly developed approaches for increasing the differentiation capacity. There still is significant variance in the results obtained by different research groups and even between different experiments carried out in the same laboratory, with the same type of cells and same general type of protocol. Derivation of new lines of human pluripotent and multipotent stem cells according to standardised protocols and in completely defined; xeno-free conditions may increase the reliability and reproducibility of research and speed up the development of potential clinical applications.
Highlights
Cardiac development in the human embryoPluripotent stem cells (embryonic stem cells and induced pluripotent stem cells) maintained in culture are commonly used for derivation of cardiomyocytes in vitro
Primitive cardiomyocyte precursors were derived from several different lines of human embryonic stem cells (HES3, H9 and MEL1) by targeted differentiation using a combined protocol comprised of treatment with Activin A/bone morphogenetic protein 4 (BMP4) followed by inhibition of Wingless/INT ligand (Wnt) signaling [67]
Components of the one methodology may be included in the other (e.g. GSK3 inhibitor pretreatment typical of the Wnt signalling modulation protocol may be included in the Activin A/BMP4 protocol)
Summary
Pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells) maintained in culture are commonly used for derivation of cardiomyocytes in vitro. The specification of the cardiogenic lineage occurs mainly via cell-cell interaction between the cells of the endoderm and the mesoderm [24,25,26]. The heart tube is formed in the 3rd gestational week. It is capable of rhythmical contraction in peristaltic waves by day 2223 of pregnancy and maintains a steady blood flow in the embryo by gestation week 4-5 [reviewed in 29]. Defects in cardiac and vascular development occurring in the first few weeks of pregnancy may cause early embryo loss, whereas defects occurring later (e.g. at the time when septation normally takes place) may result in congenital heart defects [reviewed in 29, 30]
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