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Circulating traveling waves rapidly pace and mature hiPSC-derived cardiomyocytes in self-organized tissue ring

ABSTRACT: Directed differentiation methods allow acquisition of high-purity cardiomyocytes (CMs) differentiated from human induced pluripotent stem cells (hiPSCs); however, their immaturity characteristic limits their application for drug screening and regenerative therapy. The rapid electrical pacing of cardiomyocytes have been used for efficiently promoting the maturation of cardiomyocytes, here we describe a simple device in modified culture plate on which hiPSC-derived CMs can form three-dimensional self-organized tissue rings (SOTRs). Using calcium imaging, we show that within the ring, traveling waves (TWs) of action potential spontaneously originated and ran robustly at a frequency up to 4 Hz. After 2 weeks, SOTRs with TW training show matured features including structural organization, increased cardiac-specific gene expression, enhanced Ca2+-handling properties, an increased oxygen-consumption rate, and enhanced contractile force. We subsequently use a mathematical model to interpret the origination, propagation, and long-term behavior of the TWs within the SOTRs. The TW could also potentially be used for pacing the electrical excitable cells such as neuron and retina cells for various applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140466 | GEO | 2020/02/05

REPOSITORIES: GEO

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Project description:Despite efforts to mature human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for disease modeling and high throughput screening, cells remain immature and may not reflect adult biology. Recent advancements utilize electro-mechanical and paracrine stimulation to functionally mature cardiomyocytes, but the resulting engineered constructs continue to lack a microenvironment conducive to electrical signal propagation and maturity. Conductive polymers are attractive candidates to facilitate electrical communication between gaps in sparse hPSC-CM clusters or between hPSC-CMs to repair conduction defects. To create a conductive polymer platform for improved electrical signal propagation between hPSC-CMs and achieve electrical maturity, we electrospun poly(3,4-ethylendioxythiophene):polystyrene sulfonate (PEDOT:PSS) blended with 8% (w/v) poly(vinyl alcohol) (PVA). Matrix fiber structure remained stable over 4 weeks in buffer, stiffness remains near cardiac stiffness in vivo, and electrical conductivity scaled with PEDOT:PSS concentration. When fibroblasts were added to fibers, cells had higher initial attachment to PEDOT:PSS compared to PVA-only scaffolds, and after 5 days, over 90% of fibroblasts remained viable on PEDOT:PSS scaffolds compared to PVA-only scaffolds. Electrically excitable hPSC-CMs cultured on conductive substrates exhibited an upregulation of cardiac and muscle-related genes as opposed to non-conductive substrates. These cells further displayed increased desmoplakin (DP) localization on conductive scaffolds, indicating an improvement in the mechanical stability of our hPSC-CMs. Sarcomere organization also scaled with increasing PEDOT:PSS concentration, even in sub-monolayer cell densities, suggesting that improved organization of the contractile machinery in these cells was due to the electrical condition of the matrix. Calcium handling indicated higher calcium flux with a shorter time to peak, further suggesting improved electrical maturity, even when sub-confluent. Taken together, these data suggest that PEDOT:PSS/PVA scaffolds are stable, of a stiffness relevant to cardiomyocytes, and supportive of electrical coupling even in the absence of a monolayer, which may improve cardiac disease modeling and drug development.

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Circulating traveling waves rapidly pace and mature hiPSC-derived cardiomyocytes in self-organized tissue ring

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