N-cadherin Promotes Neural Stem Cell Differentiation, Opening New Avenues for Brain Aging and Neurodegenerative Disease Treatments

Researchers at Northeastern University have uncovered a critical role of the protein N-cadherin in the human brain's neural stem cell behavior, revealing promising implications for combating brain aging and neurodegenerative conditions. Published in Mechanobiology in Medicine, the study details how N-cadherin, a molecule responsible for cell adhesion and communication among neural stem cells, also acts as a key driver of their differentiation into specialized neurons and other central nervous system cells.

Neural stem cells, which are undifferentiated cells capable of transforming into various neuron types, are primarily located in specific brain regions such as the subventricular zone and the hippocampal subgranular zone. These areas are crucial for functions like learning and memory. However, aging diminishes their responsiveness and availability, hindering brain regenerative processes.

"As we age, neural stem cells become less responsive and fewer in number," explains Dr. Rebecca Kuntz Willits, a professor of chemical and bioengineering at Northeastern. To explore this challenge, her team focused on N-cadherin, a surface protein that facilitates cell adhesion and communication. Their goal was to understand how this protein influences neural stem cell behavior.

The scientists engineered glass surfaces coated with varying levels of lab-produced N-cadherin proteins and cultured induced pluripotent neural stem cells on these substrates. They observed that neural stem cells only adhered and survived on N-cadherin-coated surfaces, not on other proteins like E-cadherin. Intriguingly, higher concentrations of N-cadherin led to more extensive cell interactions, larger cell and nuclear size, and distinct structural changes within the cells.

One of the most striking findings was the formation of unique cytoskeletal "ring" structures in the neural stem cells, which correlated with their differentiation into neurons within 96 hours — all without adding chemical cues typically used to induce such transformation.

These results suggest that mechanical interactions mediated by N-cadherin can directly influence neural stem cell differentiation, a process known as mechanotransduction. This discovery opens up potential methods for controlling neural regeneration in the lab and developing therapies that could enhance brain repair or slow down age-related cognitive decline.

Future applications might include injectable materials mimicking N-cadherin interactions or targeted manipulation of this protein to promote brain cell growth, offering new hope for treating neurodegenerative diseases. The team’s ongoing research aims to deepen understanding of how N-cadherin-triggered mechanotransduction could be harnessed to develop innovative brain therapies.

For more details, see the full study: McKay Cavanaugh et al, 'Mechanotransductive N-cadherin binding induces differentiation in human neural stem cells,' Mechanobiology in Medicine, 2024. Link to the article

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