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arXiv:10.1101/2024.12.11.627627[2024]

Self-organizing human heart assembloids with autologous and developmentally relevant cardiac neural crest-derived tissues

xeuron.com/p/self-organizing-human-heart-assembloids-with-autologous-and-·DOI·Source·PDF

AI Summary

Neural crest cells (NCCs) are a multipotent embryonic cell population of ectodermal origin that extensively migrate during early development and contribute to the formation of multiple tissues. Cardiac NCCs play a critical role in heart development by orchestrating outflow tract septation, valve formation, aortic arch artery patterning, parasympathetic innervation, and maturation of the cardiac conduction system. Abnormal migration, proliferation, or differentiation of cardiac NCCs can lead to severe congenital cardiovascular malformations. However, the complexity and timing of early embryonic heart development pose significant challenges to studying the molecular mechanisms underlying NCC-related cardiac pathologies. Here, we present a sophisticated functional model of human heart assembloids derived from induced pluripotent stem cells, which, for the first time, recapitulates cardiac NCC integration into the human embryonic heart in vitro. NCCs successfully integrated at developmentally relevant stages into heart organoids, and followed developmental trajectories known to occur in the human heart. They demonstrated extensive migration, differentiated into cholinergic neurons capable of generating nerve impulses, and formed mature glial cells. Additionally, they contributed to the mesenchymal populations of the developing outflow tract. Through transcriptomic analysis, we revealed that NCCs acquire molecular features of their cardiac derivatives as heart assembloids develop. NCC-derived parasympathetic neurons formed functional connections with cardiomyocytes, promoting the maturation of the cardiac conduction system. Leveraging this model’s cellular complexity and functional maturity, we uncovered that early exposure of NCCs to antidepressants harms the development of NCC derivatives in the context of the developing heart. The commonly prescribed antidepressant Paroxetine disrupted the expression of a critical early neuronal transcription factor, resulting in impa

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Extract authors, key findings, references, and an executive summary using AI.

Extraction v1google/gemini-3.1-flash-lite-preview4/28/2026

Executive Summary

The authors present a new human neural crest-heart assembloid (hNCHA) platform, which integrates induced pluripotent stem cell-derived neural crest cells into existing heart organoid models. This system fills a critical gap in current 3D organoid research by successfully recapitulating the complex migration and differentiation of cardiac neural crest cells in a human-relevant context. By monitoring the integration over time, the researchers observed the NCCs differentiating into functional parasympathetic neurons, glial cells, and mesenchymal populations, all of which are essential components of the developing embryonic heart. Beyond modeling healthy development, the authors utilized the hNCHA platform to investigate the potential developmental risks of prenatal selective serotonin reuptake inhibitor (SSRI) exposure. Their findings demonstrate that SSRIs, particularly Paroxetine and Sertraline, cause significant dose-dependent downregulation of the key neural transcription factor PHOX2B. This molecular disruption leads to impaired neuronal development and altered parasympathetic functionality in the cardiac tissue, providing valuable mechanistic insights into the epidemiological link between prenatal SSRI use and increased rates of congenital heart defects. In conclusion, this study establishes the hNCHA as a sophisticated tool for both understanding early human cardiac development and conducting high-throughput drug screening. The platform's ability to model both the cellular complexity and functional performance of the developing heart represents a significant advancement for the field of developmental biology and pharmacology, offering a promising, human-relevant model for studying the etiology of congenital heart diseases and the safety of therapeutic interventions during pregnancy.

Authors

Aitor AguirrePrimary

Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA

aaguirre@msu.edu

Aleksandra Kostina

Institute for Quantitative Health Science and Engineering, Michigan State University

Artem Kiselev

Institute for Quantitative Health Science and Engineering, Michigan State University

Amanda Huang

Institute for Quantitative Health Science and Engineering, Michigan State University

Haley Lankerd

Institute for Quantitative Health Science and Engineering, Michigan State University

Sammantha Caywood

Institute for Quantitative Health Science and Engineering, Michigan State University

Ariadna Jurado-Fernandez

Institute for Quantitative Health Science and Engineering, Michigan State University

Brett Volmert

Institute for Quantitative Health Science and Engineering, Michigan State University

Colin O’Hern

Institute for Quantitative Health Science and Engineering, Michigan State University

Aniwat Juhong

Institute for Quantitative Health Science and Engineering, Michigan State University

Yifan Liu

Institute for Quantitative Health Science and Engineering, Michigan State University

Zhen Qiu

Institute for Quantitative Health Science and Engineering, Michigan State University

Sangbum Park

Institute for Quantitative Health Science and Engineering, Michigan State University

Abstract

Neural crest cells (NCCs) are a multipotent embryonic cell population of ectodermal origin that extensively migrate during early development and contribute to the formation of multiple tissues. Cardiac NCCs play a critical role in heart development by orchestrating outflow tract septation, valve formation, aortic arch artery patterning, parasympathetic innervation, and maturation of the cardiac conduction system. Abnormal migration, proliferation, or differentiation of cardiac NCCs can lead to severe congenital cardiovascular malformations. However, the complexity and timing of early embryonic heart development pose significant challenges to studying the molecular mechanisms underlying NCC-related cardiac pathologies. Here, we present a sophisticated functional model of human heart assembloids derived from induced pluripotent stem cells, which, for the first time, recapitulates cardiac NCC integration into the human embryonic heart in vitro. NCCs successfully integrated at developmentally relevant stages into heart organoids, and followed developmental trajectories known to occur in the human heart. They demonstrated extensive migration, differentiated into cholinergic neurons capable of generating nerve impulses, and formed mature glial cells. Additionally, they contributed to the mesenchymal populations of the developing outflow tract. Through transcriptomic analysis, we revealed that NCCs acquire molecular features of their cardiac derivatives as heart assembloids develop. NCC-derived parasympathetic neurons formed functional connections with cardiomyocytes, promoting the maturation of the cardiac conduction system. Leveraging this model's cellular complexity and functional maturity, we uncovered that early exposure of NCCs to antidepressants harms the development of NCC derivatives in the context of the developing heart. The commonly prescribed antidepressant Paroxetine disrupted the expression of a critical early neuronal transcription factor, resulting in impaired parasympathetic innervation and functional deficits in cardiac tissue. This advanced heart assembloid model holds great promise for high-throughput drug screening and unraveling the molecular mechanisms underlying NCC-related cardiac formation and congenital heart defects.

Key Findings (20)

  1. 1

    Key finding 1: Successfully generated human neural crest-heart assembloids (hNCHAs) by integrating hiPSC-derived NCCs into human heart organoids.

  2. 2

    Key finding 2: Integrated NCCs mimic developmental migratory behavior and persist in hNCHAs through development.

  3. 3

    Key finding 3: NCCs acquire molecular features of cardiac derivatives as hNCHAs develop.

  4. 4

    Key finding 4: Migrating NCCs colocalize with myocardial tissue and show active interaction with cardiomyocytes.

  5. 5

    Key finding 5: scRNA-seq analysis reveals transition of NCCs from undifferentiated state to neuronal or mesenchymal fates.

  6. 6

    Key finding 6: NCCs in hNCHAs contribute to outflow tract (OFT) mesenchyme, forming aorticopulmonary septal components.

  7. 7

    Key finding 7: NCC-derived neurons form extensive neurofilament networks (NEFM+) in hNCHAs.

  8. 8

    Key finding 8: NCCs differentiate into cholinergic neurons (VAChT+, CHAT+).

  9. 9

    Key finding 9: NCC-derived neurons establish functional synaptic communication with cardiomyocytes.

  10. 10

    Key finding 10: NCC presence promotes maturation of the cardiac conduction system, including atrioventricular node (AVN) cells.

  11. 11

    Key finding 11: AVN cardiomyocytes and NCCs share a glutamatergic signaling interaction.

  12. 12

    Key finding 12: NCCs differentiate into glial cells (S100B+) that associate with neuronal fibers.

  13. 13

    Key finding 13: Glial cells express markers and morphology consistent with cardiac support cells.

  14. 14

    Key finding 14: NCC derivatives show potential early valvular commitment expressing markers like MSX1 and COL1A1.

  15. 15

    Key finding 15: Early exposure of NCCs to SSRIs (e.g., Paroxetine, Sertraline) significantly downregulates PHOX2B.

  16. 16

    Key finding 16: SSRI-exposed NCCs show impaired differentiation along neuronal and glial lineages.

  17. 17

    Key finding 17: SSRI treatment disrupts parasympathetic markers (SLC18A3, NEFM, PRPH).

  18. 18

    Key finding 18: Assembloids with SSRI-treated NCCs exhibit increased beating rates, suggesting loss of cholinergic regulation.

  19. 19

    Key finding 19: SSRI exposure affects NCC differentiation specifically, rather than initial migration.

  20. 20

    Key finding 20: The hNCHA platform is a robust in vitro tool for modeling the impacts of drug exposure during early human heart development.

Discussion & Future Directions

The discussion section highlights the importance of incorporating neural crest cells (NCCs) into human heart organoid models to enhance their biological relevance. The authors explain that their hNCHA platform recapitulates early embryonic development by allowing NCCs to self-organize, migrate, and differentiate into parasympathetic neurons and mesenchymal cells. They suggest that the integration of these cells is critical for modeling the formation of the outflow tract, conduction system maturation, and neuro-cardiac junctions. The authors argue that this model offers a unique in vitro system for toxicological screening, specifically noting that their data provides the first human experimental evidence of how early SSRI exposure during development can cause significant, detrimental physiological changes, thereby establishing a pathway for further research into drug safety during pregnancy.

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