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embryonic stem cell-derived cardiac organoids via synthetic guidance

arXiv:10.1101/2025.07.09.663178[2025]
u/susan15383·DOI·Source·PDF|

AI Summary

Robotics draws inspiration from biology, particularly animal locomotion based on muscle-driven contractions. While traditional engineering assembles components sequentially, locomotive animals are built via self-organized developmental programs. Stem cells, under the right conditions, can mimic these processes in vitro, offering a pathway to develop muscle-propelled biobots in a self-organized building process. Here, we demonstrate that existent cardiogenic gastruloid protocols can produce motile aggregates from mouse embryonic stem cells, although with very limited efficiency. We then identify a novel protocol that yields contractile aggregates with higher frequency and larger contractile areas. In this novel protocol, mesendoderm induction using TGF-beta ligands is followed by cardiogenic induction with FGFs and VEGF. Synthetic organizers further control contraction localization. Aggregates developed via this protocol show enhanced motility, marking a step forward towards building motile cardiobots from self-organized biological material. This strategy opens new possibilities for designing autonomous biobots and studying the evolution of muscle-powered movement of multicellular organisms and cardiovascular development.

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

Version:· 1 version extracted
Extraction v1google/gemini-3.1-flash-lite5/15/2026

Executive Summary

This study introduces 'cardiobots', a new class of muscle-propelled biobots derived from mouse embryonic stem cells using a self-organizing developmental approach. By deconstructing and optimizing cardiogenic gastruloid protocols, the authors identified a superior mesendoderm induction strategy using Activin, BMP4, and VEGF, followed by cardiogenic maturation using FGF factors and L-Ascorbic acid. This novel protocol achieves high-efficiency formation of contractile aggregates with significantly enhanced motility compared to current standards. The authors further demonstrate that synthetic organizers can be used to control the spatial arrangement of these contractile domains. By integrating engineered cell clusters that secrete specific signaling factors, they successfully directed the development and localization of cardiac precursors, confirming the modifiability of these multicellular systems. Multivariate analyses, including PCA, reveal that motility performance is strongly correlated with contraction area and consistency, with the cardiobots protocol consistently producing highly motile phenotypes. Ultimately, this work serves as a proof-of-concept for 'developmental engineering', where stem cell potentials are steered toward desired mechanical outcomes. This research not only provides a platform for designing autonomous bio-hybrid machines but also offers a powerful comparative model to investigate the evolutionary trajectory of muscle-based locomotion and the origins of cardiovascular complexity.

Authors (8)

Christine HoFirst Author

Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Fokion Glykofrydis

Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Gaveen Godage

Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Abstract

Robotics draws inspiration from biology, particularly animal locomotion based on muscle-driven contractions. While traditional engineering assembles components sequentially, locomotive animals are built via self-organized developmental programs. Stem cells, under the right conditions, can mimic these processes in vitro, offering a pathway to develop muscle-propelled biobots in a self-organized building process. Here, we demonstrate that existent cardiogenic gastruloid protocols can produce motile aggregates from mouse embryonic stem cells, although with very limited efficiency. We then identify a novel protocol that yields contractile aggregates with higher frequency and larger contractile areas. In this novel protocol, mesendoderm induction using TGF-beta ligands is followed by cardiogenic induction with FGFs and VEGF. Synthetic organizers further control contraction localization. Aggregates developed via this protocol show enhanced motility, marking a step forward towards building motile cardiobots from self-organized biological material. This strategy opens new possibilities for designing autonomous biobots and studying the evolution of muscle-powered movement of multicellular organisms and cardiovascular development.

Fields of Study

Cardiobot EngineeringSynthetic Developmental BiologyRegenerative MedicineStem Cell BiologyTissue EngineeringCardiovascular DevelopmentBiomedical EngineeringDevelopmental BiologySynthetic BiologyBiological Sciences

Key Findings (20)

1.Existing cardiogenic gastruloid protocols generate motile aggregates at very low efficiency.

2.Limited contractile area is a primary factor restricting motility in standard cardiogenic gastruloids.

3.A novel 'cardiobots' protocol utilizes TGF-beta ligands for mesendoderm induction and FGFs/VEGF for cardiogenic induction.

Discussion & Future Directions

The discussion emphasizes the potential of using developmental engineering to create motile synthetic organisms. It highlights the success of the 'cardiobots' protocol in driving mESCs toward contractile, muscle-propelled aggregates, providing insights into the evolutionary repurposing of genetic circuits for muscular contraction and cardiovascular development. Future research directions suggested include optimizing reproducibility, enhancing body plan control via synthetic organizers, and implementing transient genetic 'kill switches' for synthetic organizers to improve experimental control and minimize unwanted metabolic load.

References (72)

  1. [1]Andersen, P. et al. (2018). Precardiac organoids form two heart fields via Bmp/Wnt signaling. Nat. Commun. 9, 3140.
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  2. [2]Argiro, L. et al. (2024). Gastruloids are competent to specify both cardiac and skeletal muscle lineages. Nat. Commun. 15, 10172.
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  3. [3]Arnellos, A. & Keijzer, F. (2019). Bodily Complexity: Integrated Multicellular Organizations for Contraction-Based Motility. Front. Physiol. 10, 1268.
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Sections

Executive SummaryAuthorsAbstractFields of StudyKey FindingsDiscussionReferences