Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation
Abstract Neuronal differentiation and maturation are crucial for developing research models and therapeutic applications. Brain-derived neurotrophic factor (BDNF) is a widely used biochemical stimulus for promoting neuronal maturation. However, the broad effects of biochemical stimuli on multiple ce...
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Nature Portfolio
2025-02-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-89330-4 |
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| author | María del Pilar Diego-Santiago María Ujué González Esther María Zamora Sánchez Nuria Cortes-Carrillo Carlos Dotti Francesc Xavier Guix Sahba Mobini |
| author_facet | María del Pilar Diego-Santiago María Ujué González Esther María Zamora Sánchez Nuria Cortes-Carrillo Carlos Dotti Francesc Xavier Guix Sahba Mobini |
| author_sort | María del Pilar Diego-Santiago |
| collection | DOAJ |
| description | Abstract Neuronal differentiation and maturation are crucial for developing research models and therapeutic applications. Brain-derived neurotrophic factor (BDNF) is a widely used biochemical stimulus for promoting neuronal maturation. However, the broad effects of biochemical stimuli on multiple cellular functions limit their applicability in both in vitro models and clinical settings. Electrical stimulation (ES) offers a promising physical method to control cell fate and function, but it is hampered by lack of standard and optimised protocols. In this study, we demonstrate that ES outperforms BDNF in promoting neuronal maturation in human neuroblastoma SH-SY5Y. Additionally, we address the question regarding which ES parameters regulate biological responses. The neuronal differentiation and maturation of SH-SY5Y cells were tested under several pulsed ES regimes. We identified accumulated charge and effective electric field time as novel criteria for determining optimal ES regimes. ES parameters were obtained using electrochemical characterisation and equivalent circuit modelling. Our findings show that neuronal maturation in SH-SY5Y cells correlates with the amount of accumulated charge during ES. Higher charge accumulation (~ 50 mC/h) significantly promotes extensive neurite outgrowth and ramification, and enhances the expression of synaptophysin, yielding effects exceeding those of BDNF. In contrast, fewer charge injection to the culture (~ 0.1 mC/h) minimally induces maturation but significantly increases cell proliferation. Moreover, ES altered the concentration and protein cargo of secreted extracellular vesicles (EV). ES with large enough accumulated charge significantly enriched EV proteome associated with neural development and function. These results demonstrate that each ES regime induces distinct cellular responses. Increased accumulated charge facilitates the development of complex neuronal morphologies and axonal ramification, outperforming exogenous neurotrophic factors. Controlled ES methods are immediately applicable in creating mature neuronal cultures in vitro with minimal chemical intervention. |
| format | Article |
| id | doaj-art-fcb564add6f0420a85782b80160795bd |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-fcb564add6f0420a85782b80160795bd2025-02-09T12:31:17ZengNature PortfolioScientific Reports2045-23222025-02-0115111610.1038/s41598-025-89330-4Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturationMaría del Pilar Diego-Santiago0María Ujué González1Esther María Zamora Sánchez2Nuria Cortes-Carrillo3Carlos Dotti4Francesc Xavier Guix5Sahba Mobini6Instituto de Micro y Nanotecnología, IMN-CNM, CSIC (CEI UAM+CSIC)Instituto de Micro y Nanotecnología, IMN-CNM, CSIC (CEI UAM+CSIC)Instituto de Micro y Nanotecnología, IMN-CNM, CSIC (CEI UAM+CSIC)Instituto de Micro y Nanotecnología, IMN-CNM, CSIC (CEI UAM+CSIC)Molecular Neuropathology Unit, Physiological and Pathological Processes Program, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAMGrup d’Enginyeria de Materials (GEMAT), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL)Instituto de Micro y Nanotecnología, IMN-CNM, CSIC (CEI UAM+CSIC)Abstract Neuronal differentiation and maturation are crucial for developing research models and therapeutic applications. Brain-derived neurotrophic factor (BDNF) is a widely used biochemical stimulus for promoting neuronal maturation. However, the broad effects of biochemical stimuli on multiple cellular functions limit their applicability in both in vitro models and clinical settings. Electrical stimulation (ES) offers a promising physical method to control cell fate and function, but it is hampered by lack of standard and optimised protocols. In this study, we demonstrate that ES outperforms BDNF in promoting neuronal maturation in human neuroblastoma SH-SY5Y. Additionally, we address the question regarding which ES parameters regulate biological responses. The neuronal differentiation and maturation of SH-SY5Y cells were tested under several pulsed ES regimes. We identified accumulated charge and effective electric field time as novel criteria for determining optimal ES regimes. ES parameters were obtained using electrochemical characterisation and equivalent circuit modelling. Our findings show that neuronal maturation in SH-SY5Y cells correlates with the amount of accumulated charge during ES. Higher charge accumulation (~ 50 mC/h) significantly promotes extensive neurite outgrowth and ramification, and enhances the expression of synaptophysin, yielding effects exceeding those of BDNF. In contrast, fewer charge injection to the culture (~ 0.1 mC/h) minimally induces maturation but significantly increases cell proliferation. Moreover, ES altered the concentration and protein cargo of secreted extracellular vesicles (EV). ES with large enough accumulated charge significantly enriched EV proteome associated with neural development and function. These results demonstrate that each ES regime induces distinct cellular responses. Increased accumulated charge facilitates the development of complex neuronal morphologies and axonal ramification, outperforming exogenous neurotrophic factors. Controlled ES methods are immediately applicable in creating mature neuronal cultures in vitro with minimal chemical intervention.https://doi.org/10.1038/s41598-025-89330-4Neuronal differentiation and maturationElectrical stimulationCharge injectionBiochemical-free stimulationNeural extracellular vesicles |
| spellingShingle | María del Pilar Diego-Santiago María Ujué González Esther María Zamora Sánchez Nuria Cortes-Carrillo Carlos Dotti Francesc Xavier Guix Sahba Mobini Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation Scientific Reports Neuronal differentiation and maturation Electrical stimulation Charge injection Biochemical-free stimulation Neural extracellular vesicles |
| title | Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation |
| title_full | Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation |
| title_fullStr | Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation |
| title_full_unstemmed | Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation |
| title_short | Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation |
| title_sort | bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation |
| topic | Neuronal differentiation and maturation Electrical stimulation Charge injection Biochemical-free stimulation Neural extracellular vesicles |
| url | https://doi.org/10.1038/s41598-025-89330-4 |
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