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High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers
Published on: March 24, 2023
Graphene Sheet-Induced Global Maturation of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells
Jiaxian Wang1, Chang Cui2, Haiyan Nan3
1National Center for Human Genetics, National Research Institute for Family Planning , Beijing 100081, China.
Insights
Human induced pluripotent stem cells (hiPSCs) differentiated on graphene substrates show enhanced maturation. This novel platform improves cardiomyocyte function and organization, paving the way for better disease modeling and regenerative medicine.
Area of Science:
- Biomedical Engineering
- Stem Cell Biology
- Cardiovascular Research
Background:
- Human induced pluripotent stem cells (hiPSCs) offer a renewable source for generating cardiomyocytes for various applications.
- hiPSC-derived cardiomyocytes (hiPSC-CMs) exhibit immature, fetal-like characteristics, limiting their utility in disease modeling and regenerative medicine.
- Current in vitro differentiation methods fail to replicate the native cardiogenesis niche's structural and mechanical cues.
Purpose of the Study:
- To develop an efficient platform for maturing hiPSC-CMs using a graphene substrate.
- To investigate the impact of a conductive biomimetic surface on cardiomyocyte development and function.
- To enhance the structural, electrophysiological, and functional properties of hiPSC-CMs.
Main Methods:
- hiPSCs were cultured and differentiated into cardiomyocytes on graphene substrates.
- Cardiac maturation was assessed by evaluating myofibril organization, conduction velocity, Ca2+ handling, and electrophysiological properties.
- RNA sequencing was employed to analyze gene expression changes, including bone morphogenetic proteins signaling.
Main Results:
- Graphene substrates supported hiPSC maintenance and differentiation into functional cardiomyocytes.
- Significant improvements were observed in myofibril ultrastructural organization and Ca2+ handling.
- Conduction velocity and electrophysiological properties were enhanced, correlating with increased connexin 43 expression.
- Bone morphogenetic proteins signaling pathways were activated during early cardiogenesis on graphene.
Conclusions:
- Electrically active graphene substrates can effectively promote the global maturation of hiPSC-CMs by mimicking the native heart's microenvironment.
- This approach offers a simple, fast, and scalable method for maturing regenerated cardiomyocytes.
- Graphene-based platforms hold significant potential for advancing cardiovascular research and therapeutic applications.
Abstract:
Human induced pluripotent stem cells (hiPSCs) can proliferate infinitely. Their ability to differentiate into cardiomyocytes provides abundant sources for disease modeling, drug screening and regenerative medicine. However, hiPSC-derived cardiomyocytes (hiPSC-CMs) display a low degree of maturation and fetal-like properties. Current in vitro differentiation methods do not mimic the structural, mechanical, or physiological properties of the cardiogenesis niche. Recently, we present an efficient cardiac maturation platform that combines hiPSCs monolayer cardiac differentiation with graphene substrate, which is a biocompatible and superconductive material. The hiPSCs lines were successfully maintained on the graphene sheets and were able to differentiate into functional cardiomyocytes. This strategy markedly increased the myofibril ultrastructural organization, elevated the conduction velocity, and enhanced both the Ca2+ handling and electrophysiological properties in the absence of electrical stimulation. On the graphene substrate, the expression of connexin 43 increased along with the conduction velocity. Interestingly, the bone morphogenetic proteins signaling was also significantly activated during early cardiogenesis, confirmed by RNA sequencing analysis. Here, we reasoned that graphene substrate as a conductive biomimetic surface could facilitate the intrinsic electrical propagation, mimicking the microenvironment of the native heart, to further promote the global maturation of hiPSC-CMs. Our findings highlight the capability of electrically active substrates to influence cardiomyocyte development. We believe that application of graphene sheets will be useful for simple, fast, and scalable maturation of regenerated cardiomyocytes.
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