Discovery shows potential for brain aging and disease therapies

Northeastern University scientists have discovered that a protein in the human brain could potentially be used to grow new neurons in the lab and enhance brain processes affected by aging or neurodegenerative diseases.

In their study, published in Mechanobiology in Medicine, the researchers discovered that the protein responsible for binding neural stem cells in the human brain, neuro-cadherin, also plays a key role in stimulating their differentiation.

Neural stem cells are early-stage, unspecialized cells that have the ability to differentiate, or develop, into various types of neurons and non-neuronal cells of the central nervous system.

In the adult human brain, these cells are primarily found in two regions: the subventricular zone—a thin layer of cells lining the fluid-filled spaces called lateral ventricles deep in the brain—and the subgranular zone. The subgranular zone is a small area within the hippocampus, a part of the brain essential for learning and memory.

“With aging, neural stem cells don’t respond the way they used to when they were young,” says Rebecca Kuntz Willits, Northeastern professor of chemical and bioengineering. “There’s fewer of them in general, and they don’t necessarily differentiate as easily.”

Willits and McKay Cavanaugh, a doctoral candidate, studied Neuro-cadherin, a protein found on cell surfaces that helps neural stem cells stick together and communicate, to understand how it affects these cells.

“We were looking for ways that the environment influences these stem cells, and if the cells interact through these molecules [of N-cadherin], how we can measure it mechanically.”

Specifically, they wanted to see if neural stem cells interacting with N-cadherin would lead to mechanotransduction activity—that is, when mechanical stimuli cause biochemical responses that regulate various cellular functions and behaviors, including differentiation.

Willits explains that this discovery could have future applications in controlling neural stem cell differentiation in laboratories to accelerate neuron growth, or in developing injectable materials that could directly impact the brain’s aging processes or fighting neurodegenerative diseases.

The scientists created glass surfaces coated with different amounts of lab-made versions of the natural N-cadherin proteins. They then cultured induced pluripotent neural stem cells—or lab-made neural stem cells—on these glass substrates.

The scientists looked at cell adhesion; changes in cells’ shape, size and structure; proliferation, or cell multiplication; and cellular mechanotransduction activity.

The experiment revealed that neural stem cells adhered and survived only on N-cadherin surfaces. The cells didn’t bind to another type of the cadherin protein—epithelial, or E-cadherin—also typically found within the subventricular zone.

The scientists noticed that the neural stem cells had more interactions with substrates containing higher concentrations of N-cadherin molecules. Cell morphology changed significantly with increased N-cadherin—both cells and their nuclei grew larger.

“You could see that the structure within the cell, the scaffolding within the cell, was altered and it was essentially making the cells look different,” Willits says. “The scaffolding was stronger and the interaction points were stronger.”

Neural stem cells developed unique “ring” structures made of protein filaments—a cytoskeletal feature not previously seen in single neural stem cells.

Without any other chemical cues, the cells began to differentiate into neurons within 96 hours.

“Usually, if we wanted to make neurons, we would add all these chemicals to the cells and push them to make neurons,” Willits says. “We didn’t do any of that [this time].”

The experiment didn’t run long enough to determine what specific type of neurons these neural stem cells would become.

This story is republished courtesy of Northeastern Global News news.northeastern.edu.