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Multi-modal refinement of the human heart atlas during the first gestational trimester

ABSTRACT: Congenital heart defects are collectively frequent and a significant burden for human health. Understanding the developmental origins of such anomalies in the first and longest-lived vital organ is key to improving diagnoses, prognoses and therapies. However, although the atlas of human cardiac cells before birth continues to benefit from increased sampling, equivalencies across different investigators’ datasets or with animal models remain tenuous. We have determined the individual transcriptomes of nearly fifty thousand human heart cells from three fetuses between post-conceptional weeks (pcw) 8-11, and enriched their initial identification with a spatial transcriptomics analysis of six slices from two stage-matched samples. Integrations across modalities, sex and time points both internally and with earlier atlases have revealed the existence of previously unidentified, transient contractile, conductive and stromal cell types and their likely lineage relationships during the first trimester. Further analyses at varying levels of spatiotemporal resolution enabled us to validate charactistics of these cardiac cells in dozens of other samples and across a wide range of cell population sizes and ages. This resource advances knowledge about cell-autonomous states and adds precision to the repertory of contextual influences, including tissular and positional, exerted by and on the diverse lineages of the developing human heart during a critical time window.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283967 | GEO | 2025/01/01

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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Multi-modal refinement of the human heart atlas during the first gestational trimester

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