Abstract
The combination of cardiomyocytes (CM) and non-myocyte cardiac populations, such as endothelial cells (EC), and mesenchymal cells (MC), has been shown to be critical for recapitulation of the human heart tissue for in vitro cell-based modeling. However, most of the current engineered cardiac microtissues still rely on either (i) murine/human limited primary cell sources, (ii) animal-derived and undefined hydrogels/matrices with batch-to-batch variability, or (iii) culture systems with low compliance with pharmacological high-throughput screenings. In this work, we explored a culture platform based on alginate microencapsulation and suspension culture systems to develop three-dimensional (3D) human cardiac microtissues, which entails the co-culture of human induced pluripotent stem cell (hiPSC) cardiac derivatives including aggregates of hiPSC–CM and single cells of hiPSC–derived EC and MC (hiPSC–EC+MC). We demonstrate that the 3D human cardiac microtissues can be cultured for 15 days in dynamic conditions while maintaining the viability and phenotype of all cell populations. Noteworthy, we show that hiPSC–EC+MC survival was promoted by the co-culture with hiPSC–CM as compared to the control single-cell culture. Additionally, the presence of the hiPSC–EC+MC induced changes in the physical properties of the biomaterial, as observed by an increase in the elastic modulus of the cardiac microtissue when compared to the hiPSC–CM control culture. Detailed characterization of the 3D cardiac microtissues revealed that the crosstalk between hiPSC–CM, hiPSC–EC+MC, and extracellular matrix induced the maturation of hiPSC–CM. The cardiac microtissues displayed functional calcium signaling and respond to known cardiotoxins in a dose-dependent manner. This study is a step forward on the development of novel 3D cardiac microtissues that recapitulate features of the human cardiac microenvironment and is compliant with the larger numbers needed in preclinical research for toxicity assessment and disease modeling.
Highlights
The development of reliable human in vitro cardiac tissues that better mimic the physiology of the human heart is critical to bridge the gap between the animal models currently used in preclinical research and the human clinical setting
We developed a 3D cardiac microtissue model using CM, endothelial cells (EC), and mesenchymal cells (MC) derived from human induced pluripotent stem cell (hiPSC) microencapsulated in alginate
HiPSC were differentiated into EC and MC, using a monolayer-based differentiation protocol developed by other authors (Giacomelli et al, 2017)
Summary
The development of reliable human in vitro cardiac tissues that better mimic the physiology of the human heart is critical to bridge the gap between the animal models currently used in preclinical research and the human clinical setting. In the postnatal period, CM represent the majority of the cardiac cells (66%), as opposed to the 30% in the adult mammalian heart (Bergmann et al, 2015) Another reason for this controversy is that divergent results have been obtained using different analytical tools. Further effort should be performed to develop protocols that enable the scalable production of a biologically relevant hiPSCderived cardiac tissue model in defined conditions for further implementation of large pharmacological screenings
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