Researchers hack the internal clock of neurons to accelerate the study of neurological diseases

The neurons that make up our brain and nervous system mature slowly, over several months. And while this may be beneficial from an evolutionary perspective, the slow growth of cells makes studying neurodegenerative and neurodevelopmental diseases – like Parkinson’s, Alzheimer’s and autism – in the laboratory quite difficult.

Currently, nerve cells derived from human pluripotent stem cells take months to reach an adult state in the laboratory – a timeline that reflects the slow development of the human brain. (“Pluripotent stem cells” have the potential to develop into many other cell types.)

New research from Memorial Sloan Kettering Cancer Center (MSK), however, has discovered a way to “hack” cells’ internal clocks to speed up the process. This work sheds new light on how cell developmental schedules are regulated.

“This slow pace of nerve cell development has been associated with the unique and complex cognitive abilities of humans,” says Lorenz Studer, MD, director of the Center for Stem Cell Biology at MSK and senior author of two recent studies published in Nature And Natural biotechnology. “Previous research has suggested the presence of a ‘clock’ in cells that determines the rate at which our neurons develop, but its biological nature has remained largely unknown until now.”

New knowledge about nerve cell development

The researchers, led by the study’s first author, Gabriele Ciceri, Ph.D., identified an epigenetic “barrier” in the stem cells that give rise to neural cells. (“Epigenetic changes” are those that do not alter the DNA code.) This barrier acts as a brake on the developmental process and determines the rate at which cells mature. By inhibiting the barrier, the scientists were able to accelerate the development of neurons, they reported January 31 in Nature.

“While studying brain development in mice, I was struck by how neurons progress through a series of stages on a very precise schedule,” says Dr. Ciceri, a principal investigator at the University’s Studer Lab. MSK Sloan Kettering Institute. “But this schedule creates a big practical challenge when working with human neurons: What takes hours and days in mice requires weeks and months in human cells.”

Furthermore, the team showed that this defining epigenetic barrier is built in neural stem cells long before they differentiate into different types of neurons. They also discovered higher levels of barrier in human neurons than in mouse neurons, which could help explain differences in the rate of cell maturation across species.

Discover fundamental biology

That such findings were made in a cancer center is not as surprising as it might seem at first glance. The Studer Lab has long worked to harness advances in stem cell biology to develop new therapies for degenerative diseases and cancer, both of which are strongly associated with aging.

Additionally, MSK has long been a leader in “basic science” research, that is, science that seeks to develop a fundamental understanding of human biology.

About half of the National Institutes of Health (NIH) budget is dedicated to funding basic scientific research, and the vast majority of drugs approved by the Food and Drug Administration in recent years involved publicly funded basic research, according to the NIH.

“All the major advances in cancer treatment in recent years (immune checkpoint inhibitor therapy, CAR T cell therapy, cancer vaccines) are all rooted in basic research,” says Joan Massagué, Ph.D. , director of Sloan Kettering. Institute and scientific director of MSK. “Sometimes it takes years for the medical relevance of a particular finding to become clear.”

“A valuable research tool”

A second study, led by Studer Lab graduate students Emiliano Hergenreder and Andrew Minotti, and published January 2 in Natural biotechnology, identified a combination of four chemicals that together can promote neuronal maturation. Called GENtoniK, this chemical cocktail both represses the epigenetic factors that inhibit cell maturation and stimulates the factors that promote it.

In addition to helping bring neurons to an adult state more quickly in the laboratory, this approach holds promise for other cell types, the researchers note.

Not only was GENtoniK shown to accelerate the maturation of cortical neurons (involved in cognitive functions) and spinal motor neurons (involved in movement), but the chemicals were also able to accelerate the development of several other cell types derived from stem cells, including melanocytes (pigment cells) and pancreatic beta cells (endocrine cells).

“The generation of human neurons in a plate from stem cells represents a unique advance in the study of brain health and disease,” the journal editors note in a research note accompanying the study. “A major obstacle in this field arises from the fact that human neurons require several months to mature during development, making it difficult to recapitulate the process in vitro. The authors provide a valuable research tool by developing a simple drug cocktail which accelerates the ripening. period of time.”

The findings could be particularly useful for modeling disorders like autism that involve problems with synaptic connectivity, Dr. Studer says.

Still, he notes, more research is needed to develop models of neurodegenerative disorders that don’t occur until very late in life, such as Parkinson’s disease, which has long been the focus of Studer’s research.

“Typically, a person is between 60 and 70 years old when the disease begins. No baby gets Parkinson’s disease,” he says. “So for these diseases, we need to be able to put the cells not only into an adult state but also into an elderly-like state. That’s something we continue to work on.”