Source-Medical-Xpress
Our nervous systems and brains are made up of slowly maturing neurons that take several months to fully mature. Furthermore, although this might be advantageous from an evolutionary perspective, the sluggish pace makes it difficult for the growth of new brain cells in the lab for research on neurodegenerative and neurodevelopmental disorders, such as autism, Parkinson’s disease, and Alzheimer’s disease.
Currently, it takes months for nerve cells created from human pluripotent stem cells to mature in the lab; this timetable is similar to the sluggish growth of the human brain. (“Pluripotent stem cells” have the capacity to differentiate into a wide variety of other cell types.)
However, a new study out of Memorial Sloan Kettering Cancer Centre (MSK) has found a technique to “hack” the internal clocks of the cells to expedite the process. Furthermore, the investigation is providing fresh insights into the regulation of the growth of new brain cells.
The director of MSK’s Centre for Stem Cell Biology and senior author of two recent studies published in Nature and Nature Biotechnology, Lorenz Studer, MD, states, “This slow pace of nerve cell development has been linked to humans’ unique and complex cognitive abilities.” “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.”
Fresh perspectives on the growth of new brain cells
The study’s first author, Gabriele Ciceri, PhD, and colleagues discovered an epigenetic “barrier” in the stem cells that develop into brain cells. (“Epigenetic changes” are those in which the DNA code remains unaltered.) This barrier controls the rate at which the cells mature and functions as a brake on the process of the growth of new brain cells. The scientists revealed their findings in Nature on January 31. They were able to accelerate the development of the neurons by blocking the barrier.
“While studying the growth of new brain cells in mice, I was struck by how neurons progress through a series of steps in a very precise schedule. 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.”
Dr. Gabriele Ciceri, a senior research scientist in the Studer Lab at MSK’s Sloan Kettering Institute
The researchers also demonstrated that neural stem cells contain this rate-setting epigenetic barrier even before they differentiate into distinct neuronal subtypes. Additionally, they discovered that human neurons have higher amounts of the barrier than mouse neurons, which could help explain why various species’ rates of cell maturation vary.
Discovering the fundamentals of biology
It may not come as a surprise at first that such findings were made at a cancer centre. The goal of the Studer Lab has always been to leverage the latest developments in stem cell biology to create novel treatments for cancer and degenerative disorders, two conditions that are closely linked to ageing.
Furthermore, MSK has a long history of being a pioneer in “basic science” research, or work that aims to develop a fundamental understanding of human biology.
The National Institutes of Health (NIH) funds fundamental science research with around half of its budget. Furthermore, the NIH reports that the great majority of medications that the FDA has authorised in recent years have involved publically financed basic research.
“Basic research is the foundation for all of the major advancements in cancer treatment that have occurred in recent years, including immune checkpoint inhibitor therapy, CAR T cell therapy, and cancer vaccines,” says Joan Massagué, PhD, Director of the Sloan Kettering Institute and Chief Scientific Officer of MSK. “Sometimes it can take years for the medical relevance of a particular discovery to become clear.”
“A useful research instrument”
In a second study, which was led by graduate students Emiliano Hergenreder and Andrew Minotti of the Studer Lab and was published on January 2 in Nature Biotechnology, four substances were found to work in concert to accelerate neuronal maturation. The chemical cocktail, known as GENtoniK, simultaneously stimulates factors that promote cell maturation and represses epigenetic factors that prohibit it.
The method shows promise not only for accelerating the maturation of neurons in the lab but also for other cell types, the researchers observe.
In addition to being demonstrated to hasten the maturation of spinal motor neurons, which are involved in movement, and cortical neurons, which are involved in cognitive functions, GENtoniK was also found to hasten the development of various other stem cell-derived cell types, such as melanocytes, which are pigment cells, and pancreatic beta cells, which are endocrine cells.
A research briefing accompanying the findings notes that “the generation of human neurons in a dish from stem cells provides a unique inroad into the study of brain health and disease,” according to the journal editors. “The fact that human neurons take many months to grow during development presents a significant challenge to the science as it makes it challenging to replicate the process in vitro.
The authors create a straightforward pharmacological combination that accelerates the maturation period, which offers a useful research tool.”
According to Dr. Studer, the results may be especially useful in modelling illnesses such as autism that entail issues with synaptic connection.
However, he points out that more study is required to create models of neurodegenerative illnesses that manifest extremely late in life, such Parkinson’s disease, a long-standing area of interest for Studer.
“The condition usually manifests in a person between the ages of 60 and 70. Parkinson’s does not affect babies,” he claims. Therefore, we must be able to age the cells in addition to putting them in an adult condition in order to treat those disorders. That is something we are still working on.
