Epigenetic Barrier in Progenitor Cells Controls Neuronal Maturation Rate

Neurons mature slowly. Currently, nerve cells derived from human pluripotent stem cells take months to reach an adultlike state in the lab—a timeline that mirrors the slow pace of human brain development. This makes experiments to study neurodegenerative and neurodevelopmental diseases—like Parkinson’s disease, Alzheimer’s disease, and autism—challenging.

New research led by Memorial Sloan Kettering Cancer Center (MSK) has uncovered not only that an epigenetic developmental program that sets the timing of human neuronal maturation, but also a way to speed up the process. The team’s findings also reveal that the rate at which human neurons mature is set well before neurogenesis.

“This slow pace of nerve cell development has been linked to humans’ unique and complex cognitive abilities,” said Lorenz Studer, MD, director of MSK’s Center for Stem Cell Biology. “Previous research has suggested the presence of a ‘clock’ within cells that sets the pace of our neurons’ development, but its biological nature had largely remained unknown—until now.”

This work is published in Nature in the paper, “An epigenetic barrier sets the timing of human neuronal maturation.”

The team first developed an hPSC-based approach to synchronize the birth of cortical neurons in vitro. They observed that the cells’ maturation was limited by the retention of specific epigenetic factors. The authors noted, “Transient inhibition of EZH2, EHMT1 and EHMT2, or DOT1L at progenitor stage primes newly born neurons to rapidly acquire mature properties upon differentiation.”

“While studying brain development in mice, I was struck by how neurons progress through a series of steps in a very precise schedule,” said author Gabriele Ciceri, PhD, a senior research scientist in the Studer lab at MSK’s Sloan Kettering Institute. “But this schedule creates a big practical challenge when working with human neurons—what takes hours and days in the mouse requires weeks and months in human cells.”

Furthermore, the team showed that this rate-setting epigenetic barrier is built into neural stem cells well before they differentiate into different types of neurons. They also found higher levels of the barrier in human neurons compared with mouse neurons, which may help explain differences in the pace of cell maturation in different species.

A second study, published last month in Nature Biotechnology titled, “Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons,” and also led by graduate students in the Studer lab, identified a combination of four chemicals that together can promote neuronal maturation. Dubbed GENtoniK, the chemical cocktail both represses epigenetic factors that inhibit cell maturation and stimulates factors that promote it.

Along with helping to bring neurons to an adultlike state faster in the lab, the approach holds promise for other cell types, the researchers noted.

Not only was GENtoniK shown to speed 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 types of cells derived from stem cells, including melanocytes (pigment cells) and pancreatic beta cells (endocrine cells).

“The generation of human neurons in a dish from stem cells provides a unique inroad into the study of brain health and disease,” the journal editors noted in a research briefing that accompanied the study. “A major obstacle in the field arises from the fact that human neurons require many 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 that speeds up the maturation timeframe.”

The findings could be particularly helpful in modeling disorders like autism that involve problems with synaptic connectivity, Studer said. Still, he noted, additional research is needed to develop models of neurodegenerative disorders that don’t occur until very late in life, such as Parkinson’s disease.

“Typically, a person is 60 to 70 years old when the disease begins. No baby gets Parkinson’s,” he says. “So, for those diseases, we need to be able to put the cells not just into an adult state but into an aged-like state. That’s something we’re continuing to work on.”