Human pluripotent stem cell-derived cardiomyocytes (hPSC-derived CMs) are currently an area of active interest to biomedical researchers due to the vast number of potential applications they have in drug discovery [
Human cardiomyogenesis is a complex sequential process which goes through different numerous developmental stages. The major phases in cardiac development are as follows: (1) establishment of mesoderm formation (from hPSCs); (2) patterning toward cardiac mesoderm; (3) cardiac mesoderm formation; (4) cardiomyocyte development and maturation [
Recent advances in the development of novel or improved differentiation protocols for hPSC-derived CMs [
Bottleneck 1: Compound screening, available testbeds and druggable targets
In recent years there is an ongoing debate about how small-molecule compounds should be screened for cardiomyogenic properties [
Compound screening. Over the years both synthetic and natural small-molecule compounds have been identified as inducers of cardyomyogenesis [
Available testbeds. Nowadays biomedical researchers have access to various stem cell lines which can be used to produce stem-cell-derived cardiomyocytes for applications like drug discovery and regenerative medicine or to probe the signaling pathways behind cardiomyogenesis. However, the need to choose one characterized cell line from a pool of available stem cell types (e.g. murine or human; embryonic or induced pluripotent) can be rather daunting and results obtained in animal cell lines may not be translatable to human cell lines. For example, the cardiomyogenic effect of ascorbic acid was first discovered in stably transfected EGFP-mouse embryonic stem cells back in 2003 [
Druggable targets. The discovery of new druggable targets influencing cardiac differentiation is often coupled with breakthroughs in small molecule HTS. However, the opposite may also be true [
Bottleneck 2: Cardiomyocyte maturation in vitro
A common setback of most currently used differentiation protocols for hPSC-derived CMstoday is the insufficient cell culture maturation in vitro [
Presently we face more than one bottlenecks in development of potential applications of small molecule-mediated cardiomyogenesis in hPSCs for large scale production of human CMs for the purposes of drug discovery, safety pharmacology, disease modeling and regenerative medicine. Firstly, the spacial-temporal complexity of cardiomyogenesis in human stem cells significantly slows down the identification of differentiation pathways and differentiation modulating molecules, that may successfully be manipulated used in a large-scale production. In addition, the cost of technology transfer alone may prove to be prohibitive for many currently developed differentiation protocols. Secondly, without the methodology for reliable assessment of hPSC-derived CMs for adult-like morphological and electrophysiologyical properties, their potential use is questionable, especially in the field of regenerative and reparative medicine. It could be expected that those problems could be solved using an interdisciplinary approach to human cardiomyocyte differentiation complemented by tissue engineering.
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