Building and shaping an embryo requires the concerted effort of numerous signals and molecular interactions during development. One essential aspect of this process is collective cell migration, where clusters of cells move together in a coordinated fashion by interacting with diverse stimuli from their environment. Despite the importance of this process in the animal kingdom, the underlying mechanisms are still not fully understood. Novel findings published in Nature Materials from the Barriga group at the Cluster of Excellence Physics of Life (PoL) at Dresden University of Technology highlight that electric fields can drive cells of the neural crest to migrate during development. This groundbreaking research also represents the first experimental demonstration of how electric fields emerge in a developing embryo, through mechanical stretching of cell membranes to create an electrical gradient.

As an embryo grows, there is a continuous stream of communication between cells to form tissues and organs. Cells need to read numerous cues from their environment, and these may be chemical or mechanical in nature. However, these alone cannot explain collective cell migration, and a large body of evidence suggested that movement may also happen in response to embryonic electric fields. How, and where these fields are established within embryos, was unclear until now. “We have characterised an endogenous bioelectric current pattern, which resembles an electric field during development, and demonstrated that this current can guide migration of a cell population known as the neural crest”, highlights Dr. Elias H. Barriga, the corresponding author who led the study. Initially, Dr Barriga and his team began research on the neural crest at the former Gulbenkian Institute of Science (IGC) in Oeiras, Portugal before continuing research in Dresden, establishing a group at the Cluster of Excellence Physics of Life.

The neural crest is an essential part of the embryo, and this region of cells forms the bones of our face and neck, as well as parts of the nervous system. Dr. Barriga and colleagues found that cells of the neural crest are directed by internal electric fields during development, much like drivers follow the signals of a traffic warden. The group discovered that through this process, known as electrotaxis, cells can sense direction from electric fields generated inside the embryo and move accordingly. This observation had been previously limited mostly to the study of cultured cells, but now was demonstrated within a developing embryo. But an important question remained unanswered: How are the cells interpreting these currents and translating them into directional movement?

To answer this question, Dr. Barriga and his team identified an enzyme known as voltage-sensitive phosphatase 1 (Vsp1) found in neural crest cells. Due to the versatile structure of Vsp1, it seemed capable of both sensing and transducing electrical signals. To confirm that Vsp1 is required for electrotaxis, the researchers created a defective version of the enzyme and showed that collective electrotaxis was impaired in cells injected with this copy. “For me, applying tools I developed to target gene expression in the context of bioelectricity was highly rewarding, and I look forward to its potential being fully exploited” highlighted Dr. Sofia Moreira, a postdoctoral scientist who worked on the study. Contrary to expectations, Vsp1 did not appear to be relevant for movement itself, but instead could specifically convert electric current gradients into directional and collective migration. This is a unique observation, as most enzyme sensors are required for movement itself, making it difficult to study their role in guiding direction. Going one step further, the authors also proposed how the electric fields may form; through mechanical stretching of a region known as the neural fold. As the cells in this region stretch, this causes activation of specific ion channels, resulting in a voltage gradient. Then, when cells encounter this gradient, Vsp1 transforms the electrical signals into a directional cue, telling the cells which way to go, and collective cell migration results.

This is the first experimental evidence to suggest that electric fields emerge along the path where neural crest cells migrate, and to explain their mechanism of origin. These discoveries highlight a valuable contribution that bioelectricity provides during embryonic development. By advancing our knowledge of electrotaxis within a living animal, this research opens new possibilities for mimicking developmental processes in the lab, with accuracy greater than ever before. The first author of the study, postdoctoral scientist Dr. Fernando Ferreira notes “This paper bridges an important, decades-old gap in bioelectricity research, and it is deeply rewarding to be part of the ongoing renaissance in developmental bioelectricity”. However, research into the mechanisms of electrotaxis is still ongoing. “In a broader perspective, we have now introduced another player into the intricate process of tissue morphogenesis” notes Dr. Barriga. “The question is now, how does this fit into already established frameworks of mechanical and chemical cues during embryogenesis?”. Beyond development, similar mechanisms might also exist during wound healing and cancer progression. Understanding how electric fields guide cell migration could even inspire potential novel strategies in tissue engineering and regenerative medicine. However, further research is required to expand on the role of electric fields in cellular behaviour, and increase our understanding of the physics behind living systems.

Investigators: Fernando Ferreira, Sofia Moreira, Min Zhao, and Elias H. Barriga

Funding: This work was supported by grants from the European Research Council Starting Grant (ERC-StG) under the European Union’s Horizon 2020 research and innovation programme, grant agreement no. 950254 (to E.H.B.); The European Molecular Biology Organization (EMBO) Installation Grant, project no. 4765 (to E.H.B.); EMBO Young Investigator program, project no. 5248 (to E.H.B.); EMBO postdoctoral fellowship, ALTF 27-2020 (to F.F.); La Caixa Junior Leader Incoming, no. 94978 (to E.H.B.); and Fundação para a Ciência e a Tecnologia (FCT) postdoctoral fellowship, 2020.00759.CEECIND (to S.M.). Research by E.H.B. was also supported by the IGC, Fundação Calouste Gulbenkian (FCG), start-up grant I-411133.01, and from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy (EXC 2068, 390729961), Cluster of Excellence Physics of Life of TU Dresden.

Study: Fernando Ferreira, Sofia Moreira, Min Zhao, and Elias H. Barriga. Nature Materials. DOI: 10.1038/s41563-024-02060-2

About the Cluster of Excellence, Physics of Life:
Physics of Life (PoL) is one of three clusters of excellence at TU Dresden. It focuses on identifying the physical laws underlying the organization of life in molecules, cells, and tissues. In the cluster, scientists from physics, biology, and computer science investigate how active matter in cells and tissues organizes itself into given structures and gives rise to life. PoL is funded by the DFG within the framework of the Excellence Strategy. It is a cooperation between scientists of the TU Dresden and research institutions of the DRESDEN-concept network, such as the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG), the Max Planck Institute for the Physics of Complex Systems (MPI-PKS), the Leibniz Institute of Polymer Research (IPF) and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR). www.physics-of-life.tu-dresden.de

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