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Modeling acute myocardial infarction in vitro using mature and ventricular hESC-derived cardiomyocytes by FGF4 and ascorbic acid treatment

ABSTRACT: hPSC-CMs resemble immature embryonic or fetal CMs rather than mature adult CMs, and have limitations in disease modeling and pharmacological studies. Therefore, hPSCs-derived mature and ventricular CMs are required for more accurate in vitro modeling of adult-onset cardiac disease and drug discovery. FGF4+AA-treated hESC-CMs robustly released acute myocardial infarction (AMI) biomarkers (cTnI, CK-MB, and myoglobin) into culture medium in response to hypoxic injury. Hypoxia-responsive genes related to cellular responses to glycolytic processes, oxygen levels, HIF-1 signaling, apoptotic processes, and regulation of cell death including potential cardiac biomarkers proved in clinical studies in the diagnosis and prognosis of coronary artery diseases were induced in FGF4+AA-treated hESC-CMs in response to hypoxia based on transcriptome analyses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171824 | GEO | 2021/04/11

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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Modeling acute myocardial infarction in vitro using mature and ventricular hESC-derived cardiomyocytes by FGF4 and ascorbic acid treatment

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