Current Events: Bioelectrical Gradients Guide Stem Cell Morphology

The dance of development is electric. Bioelectrical gradients choreograph embryonic growth, signaling to stem cells what cell types they should become, where they should travel, who their neighbors should be, and what structures they should form.¹ The intensity and location of these signals serve as an electrical scaffold to map out anatomical features and guide development. Bioelectricity also shapes tissue regeneration.² Tapping into these mechanisms is of special interest to researchers who grapple with the challenge of regenerating injured nerves.³ 

One such curious team from Stanford University and the University of Arizona recently reported a new approach using electrically conductive hydrogels to induce differentiation of human mesenchymal stem cells into neurons and oligodendrocytes in vitro.⁴ Their findings, published in the Journal of Materials Chemistry B, provide important proof of principle for future studies of biocompatible materials to electrically augment transplanted and endogenous cells after injury. 

“Our lab uses different polymers to interact with the nervous system. We think there’s a window after injury that seems to mirror development,” said Paul George, a physician scientist at Stanford University and coauthor of this study. “Since a lot of development is guided by gradients and electric fields, we tried to create a hydrogel that had a gradient like you might see in the developing body that could guide stem cells to differentiate certain ways or form certain structures.”

Hydrogels are a popular biocompatible material for tissue engineers trying to mimic the native environment of cells. They retain large volumes of water, their stiffness and three-dimensional properties can be controlled, and they can be packed with electrically conductive fillers. “There are a lot of great potential applications for regenerative medicine, in vitro modeling, and potentially biomanufacturing,” said Nisha Iyer, a biomedical engineer at Tufts University, who was not involved in the study. “The idea that you could use electrical fields and 3D mechanical properties to impact stem cells without having to use different kinds of biomolecules or expensive growth factors to drive differentiation is hugely motivating.”

George and his team identified a specific differentiation pattern depending on the proximity of the stem cells to uniform versus varying electrical fields. Cells in the center of the hydrogel differentiated towards an oligodendrocyte lineage in response to a constant electric field, whereas those on the periphery tended to differentiate into neurons in response to a less intense, varying electric field. George’s study is unique because most in vitro studies of bioelectricity for neural regeneration focus on static electric fields rather than gradients. Spatial control of electrical gradients has the potential to mimic those found during development and aid neural regeneration following stem cell transplantation in future studies. 

“This is a nice proof of principle study. I think there is still quite a bit of additional work needed before we can use this practically in labs,” Iyer said. Although preliminary, this works takes the important first step for future transplantation studies of stem cells plus conductive gradient hydrogels, which could interact with the injured nervous system to potentially improve recovery. “This platform was our initial foray into trying to control those gradients and understand the developmental cues a little better,” George said. “There’s so much that’s still unknown and if we can turn back the clock a little bit, maybe we can help patients who have peripheral nerve injury or stroke recover a little better.”

References

1. Levin M, Stevenson CG. Regulation of cell behavior and tissue patterning by bioelectrical signals: Challenges and opportunities for biomedical engineering. Annu Rev Biomed Eng. 2012;14:295-323.
2. Mathews J, Levin M. The body electric 2.0: Recent advances in developmental bioelectricity for regenerative and synthetic bioengineering. Curr Opin Biotechnol. 2018;52:134-144. 
3. Oh B, et al. Modulating the electrical and mechanical microenvironment to guide neuronal stem cell differentiation. Adv Sci. 2021;8(7):2002112.
4. Song S et al. Conductive gradient hydrogels allow spatial control of adult stem cell fate. J Mater Chem B. 2024;12(7):1854-1863.