Revolutionary Cell Transplant Restores Brain Function In Huntington's Disease

Huntington’s disease is an inherited condition that slowly destroys brain cells, causing problems with movement, memory and behaviour. This study showed that transplanting human-derived brain support cells (called glia) into adult mice with the disease helped improve symptoms, protect neurons and slow the progression of the disease. This paves the way for new forms of treatment in the future.

Huntington’s disease (HD) is a rare but devastating genetic condition that causes the progressive degeneration of neurons in the brain. It is inherited, passed from parents to children through a defective gene called huntingtin (Htt). This gene has an abnormal repeat of the genetic code (CAG) that is much longer than normal, leading to the malfunction and death of nerve cells.

The first damage to the brain appears in a region called the neostriatum, with the loss of cells called medium spiny neurons (MSNs), and then the problem spreads to the cerebral cortex, which is responsible for functions such as thinking, memory and controlling movement. This leads to the typical symptoms of the disease: involuntary movements, cognitive problems and emotional changes.

For a long time, scientists have tried to find ways to treat Huntington's disease by focusing on saving the affected neurons, either by trying to reduce the amount of the defective protein huntingtin or by using nerve tissue transplants. However, these strategies have faced difficulties and have not yet produced effective solutions.

In recent years, researchers have begun to pay more attention to another type of brain cell: glial cells. These cells, which support and protect neurons, also appear to be involved in the progression of the disease and may actively contribute to brain damage.

To further investigate the role of glia, researchers developed a model in which mice with Huntington’s disease are transplanted shortly after birth with human glial progenitor cells (hGPCs).

These cells are taken from developing human tissue and have the potential to develop into astrocytes, an important type of glial cell. The goal was to replace the defective glia in the mice with healthy ones from human donors.

Sections of a normal brain (left) and one affected by Huntington’s disease (right) with brain shrinkage and enlargement of the ventricles.

The studies showed that this replacement, called chimerization, was able to slow the progression of the disease and improve the behavior of the mice. They showed less hyperexcitability in the neurons and increased the complexity of the network of connections in the brain.

Based on this initial success, the scientists decided to test whether the transplantation of human glial progenitor cells (hGPCs) could also help when done in adult mice, that is, after the initial phase of brain development.

In the new study, they injected these cells into the brains of young adult mice with Huntington’s disease and observed positive results. The transplant allowed the human glial cells to integrate well into the animals’ brains and helped delay the onset of the motor and cognitive symptoms typical of the disease, in addition to increasing the survival of the mice.

When examining the brains of these animals, the researchers noticed that the neurons of the Huntington's disease mice that received the graft showed signs of recovery.

This image shows how scientists were able to insert and spread human brain cells into an experimental mouse model. Each panel of the figure shows a different type of analysis. In part A, we see a stain where red (hNA) marks the human cells and blue (DAPI) shows the nuclei of all the cells. This shows how the human cells spread into the mouse brain tissue. In drawing B, a red dotted map indicates the distribution of human cells in the region of the brain that was studied. Graph C compares the percentage of human cells that transformed into two types of nervous system cells: astrocytes (marked in blue, GFAP+) and oligodendrocytes (marked in red, Olig2+), showing that the majority became oligodendrocytes. Panels D, E and F show examples of these cells in the tissue, with the colors marking the cell types and arrows pointing to where the human cells are mixed with the mouse tissue. Finally, G shows that these human cells can also express the protein huntingtin (HTT), linked to Huntington's disease. Using advanced techniques such as single-nuclear RNA sequencing (snRNA-seq), they identified that the pattern of gene activation in neurons began to resemble the normal pattern more closely, particularly in genes linked to the structure and functioning of connections between neurons.

In addition, the analyses showed that the treated neurons had greater complexity in their dendrites (the “branches” of the cells that receive signals) and a greater number of dendritic spines (small structures that help communication between nerve cells).

In summary, the results of this study show that transplanting human glial cells into adult brains with Huntington’s disease may be a promising strategy to slow the progression of the disease, help restore the structure and function of neurons, and improve the quality of life of patients.

This approach opens up new possibilities for treatments, not only for Huntington’s disease, but potentially for other neurodegenerative diseases in which glia play an important role.

This image shows how transplanting human glial progenitor cells (hGPCs) helped mice with Huntington's disease (R6/2 model) improve in different tests of behavior, coordination, and even survival. At the top of the figure, we have drawings illustrating three tests performed on the animals: the first (open-field exploration) assesses how much the mouse moves when exploring an open space; the second (elevated plus maze) assesses anxiety, measuring how much the animal enters open arms of an elevated maze; and the third (novel object recognition) tests memory by seeing how much time the animal spends exploring a new object. In the graphs below: A shows that mice with Huntington's disease HD (R6/2) move much less, but those that received the cells (R6/2 + cell) walk more, improving slightly. B shows that R6/2 mice enter the open arms of the maze more, but the transplant does not change this anxious behavior much. Figure C shows that in the novel object test, the treated mice spent more time exploring the object, showing improved memory. Figure D shows the rotarod test, where the mice have to balance on a rotating pole: those treated with hGPCs took longer to fall, indicating better motor coordination. Finally, Figure E shows a survival graph: the mice that received the cells lived, on average, two weeks longer than the untreated ones. In short, this figure illustrates that the transplantation of human glial cells helped mice with HD to move better, have better memory and live longer.

READ MORE:

Human glial progenitors transplanted into Huntington disease mice normalize neuronal gene expression, dendritic structure, and behavior

Carlos Benitez Villanueva, Nguyen P.T. Huynh, John N. Mariani, Benjamin Mansky, Ashley Tate, Signe Syshøj Lorenzen, Devin Chandler-Militello, Abdellatif Benraiss, and Steven A. Goldman

Cell Reports, Volume 44, Issue 6115762 June 24, 2025

DOI: 10.1016/j.celrep.2025.115762

Abstract:

Neonatal glial replacement delays disease progression in mouse models of Huntington’s disease (HD), in which glial dysfunction is prominent. Here, we ask if transplanting human glial progenitor cells (hGPCs) into adult R6/2 HD mice can ameliorate the phenotype, and how diseased host neurons are affected by healthy glia. We find that the introduction of hGPCs into the striata of adult R6/2 HD mice indeed slows their motor and cognitive decline and extends survival. Single-nucleus RNA sequencing (snRNA-seq) reveals that while genes associated with synaptic development and structure are downregulated in R6/2 striatal neurons, their transcription is partially rescued by healthy glia. Rabies labeling reveals that while dendritic complexity and spine density are deficient in R6/2 striatal neurons, each is largely restored by hGPC engraftment. These findings suggest that glial replacement in HD leads to partial normalization of neuronal gene expression, along with a restoration of dendritic complexity and delay in disease progression.