A new study shows that old and damaged glial support cells of the brain can be replaced by young and healthy ones. The discovery has potential for treating such disorders as Huntington’s disease, amyotrophic lateral sclerosis (ALS) and schizophrenia.
When cells in the brain age, become defective or fail to otherwise function properly, it can lead to the development of a broad variety of neurodegenerative and neuropsychiatric diseases.
For example, disorders such as Huntington’s disease and schizophrenia are associated with dysfunction in the astrocytes, a type of glial support cell in the central nervous system that ensures that the neurons in the brain can effectively communicate with one another.
Researchers have hoped to be able to replace dysfunctional glial cells with healthy glial cells for many years and have now identified what is required to successfully replace and restore glial cells in the adult brain.
The research shows that the age of the transplanted cells is the decisive factor – even more so than whether the cells being replacing are diseased.
Young progenitor cells replace old cells in the brain naturally, so that getting young transplanted glial cells to replace those that do not work properly may open up potential treatment avenues for people with disorders such as Huntington’s disease, schizophrenia and ALS.
“Based on our many years of research and these new results, we are now planning the first clinical trials with humans. We have been in contact with the United States Food and Drug Administration regarding our plans and are doing what is needed from the regulatory standpoint to progress to clinical trials,” explains a researcher behind the study, Steven Goldman, a Professor of Neurology in the Center for Translational Neuromedicine at both the University of Copenhagen and the University of Rochester Medical Center in the United States.
The research has been published in Nature Biotechnology.
Many years of research
Steven Goldman and colleagues already showed a few years ago that when glial progenitor cells were transplanted into the brains of mice with Huntington’s disease, the transplanted cells matured as astrocytes and significantly improved the health of the mice and delayed the development of the disease.
“These experiments showed that diseased glial cells could be replaced by healthy glial cells. However, that study only showed that human cells could replace mouse cells, but that was no guarantee that human glial cells could replace other human cells,” says Steven Goldman.
He elaborates that to use a cell replacement strategy to treat people with Huntington’s disease requires showing that healthy human glial cells can actually outcompete diseased human glial cells.
Induced glia to fluoresce
To determine the decisive factors for how transplanted glial cells can outcompete existing glial cells in the brain, the researchers performed a new experiment in which they first engrafted human glial precursors carrying the Huntington’s mutation into baby mice. In addition, the researchers labelled the glial cells with a fluorescent gene so that the cells glowed red when viewed under the microscope.
When the mice reached the age of 30 to 40 weeks, during which time the transplanted Huntington’s disease glia outcompeted the mouse cells to colonise the brains with the diseased human glia, the researchers then injected healthy human glial cells into their brains.
Both the healthy and Huntington’s diseased glial cells were produced from embryonic stem cells derived from fertilised eggs of the same mother, with one set of cells having the genes for Huntington’s disease and the other not. The researchers tagged the healthy glial cells with another fluorescent gene that glows green.
The researchers discovered that, after a few months, the healthy glial cells – fluorescing green - replaced the diseased red-fluorescent glial cells.
“This showed that healthy human glial cells can outcompete and replace diseased human glial cells in the adult brain and indicated that this might well be an effective strategy for treating people with Huntington’s disease. But at the same time, this experiment did not define whether the competitive success of the healthy cells was because the cells were healthy or whether it was simply because they were younger,” says Steven Goldman.
Young cells replace the aged and diseased ones
To explore this aspect in greater depth, the researchers carried out another experiment in which they performed serial transplants from the same cell line of healthy glial cells into otherwise healthy mice, over half a year apart.
The first was given to the mice within 48 hours of birth, and the second was frozen until thawed 7 months later and then transplanted into the same site as the first injection.
Again, the already-resident (older) and newly transplanted (younger) glial cells were labelled with fluorescent genes in different colours.
Goldman and his group – and in particular Ricardo Vieira, PhD student in the lab who is now a staff scientist at Novo Nordisk – found that even though the cells used were both healthy and of exactly the same source, their only difference being in their age, the younger cells (the ones thawed out and transplanted at 7 months) still outperformed the older cells in the mice brains.
“The young progenitor cells outcompeted the older cells just as effectively as healthy cells outcompeted diseased cells. It turned out that the age of the cells was the decisive factor in whether they could replace existing cells, not so much the disease state of the host cells” explains Steven Goldman.
Awaiting evaluation from FDA
Because of that, the researcher think that this discovery is relevant not only to Huntington’s disease, but also for other brain diseases due to glial cell dysfunction. This should really expand the range of neurological conditions that we can treat using a glial cell replacement approach,
The researchers also compared the genetic expression patterns of both the healthy and Huntington's cells and the old and young cells so as to identify the decisive difference between the winners and losers– with the aim of understanding the underlying processes during cell–cell competition in the human brain before the first trials with people.
“A few years ago, we established a spin-out company – which was subsequently acquired by another company, Sana Biotechnology – that focuses on producing the cells needed for human trials of this approach. Our initial glial disease targets include not only Huntington’s disease but also progressive multipole sclerosis and certain childhood diseases of the brain’s white matter as well. Now we are awaiting evaluation of our plans by the United States Food and Drug Administration before trials in the United States can begin, and we hope that we can soon bring this approach back to Denmark as well,” concludes Steven Goldman.
