Bone marrow transplant eases brain, heart deficits in FA mice
Donor-derived cells transfer healthy mitochondria to frataxin-deficient cells
Written by |
Replacing myeloid cells — a group of immune cells that includes microglia in the brain and spinal cord and macrophages in other tissues — with healthy, donor-derived cells improved neurological and heart abnormalities in a mouse model of Friedreich’s ataxia (FA), a U.S. study found.
Microglia and macrophages can become dysfunctional when frataxin (the protein deficient in FA) is lacking, and may contribute to inflammation and tissue damage. After a bone marrow transplant, donor-derived cells replaced many of these cells in the brain and heart of FA mice and appeared to provide another benefit: transferring healthy mitochondria (the structures cells rely on to produce most of their energy) to neighboring cells affected by frataxin deficiency.
The transfer was associated with changes in genes involved in energy production and a partial restoration of mitochondrial proteins. Treated mice also grew better and survived longer, while female mice showed improvements in movement, strength, coordination, and heart function.
“These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement” and support hematopoietic transplantation — such as bone marrow transplant — for FA and other mitochondrial disorders, the researchers wrote.
The study, “Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease,” was published in Nature Communications.
Gene mutation
FA is caused by mutations in the FXN gene that lead to a shortage of frataxin. Without enough frataxin, mitochondria cannot function properly, disrupting energy production, promoting iron buildup, and damaging oxygen-containing molecules. Nerve cells and heart muscle, which have high energy demands, are among the tissues most affected, leading to common FA symptoms.
Although neurological problems in FA are mainly linked to nerve cell loss, inflammation also appears to contribute. Frataxin-deficient microglia can become overly inflammatory and lose some of their normal protective functions, while similar changes in macrophages may contribute to heart disease and other FA-related complications.
Bone marrow transplant replaces blood-forming stem cells with healthy donor cells, which can give rise to new immune cells throughout the body. These include microglia-like cells in the brain and spinal cord (the central nervous system) and macrophages in the heart and muscle.
Earlier studies in FA mice suggested that transplantation could be beneficial, but previous approaches used high-dose, whole-body irradiation and achieved relatively poor replacement of microglia in the brain.
A team of researchers at Stanford University developed a different conditioning regimen (treatment given before transplant to make room for donor cells) using busulfan and PLX3397, a drug that helps clear existing microglia and macrophages.
The team has now tested the approach in YG8-800 mice, an FA model that reproduces key features of the disease. The mice received busulfan before a bone marrow transplant from donors with normal frataxin levels, followed by PLX3397 to promote replacement of resident myeloid cells.
Five months later, fluorescent tracking showed that donor-derived cells had extensively repopulated affected tissues. In the brain, they accounted for more than 80% of microglia-like cells, while donor-derived macrophages became highly established in the heart.
A separate fluorescent marker tracking donor mitochondria was detected outside donor-derived cells in both tissues, providing evidence that mitochondria had moved from the donor immune cells into neighboring cells.
In the brain, FA mice had about three times as many cells carrying the donor mitochondrial marker as healthy mice (12.7% vs. 4.19%), suggesting FA cells may be more likely to take up or retain donated mitochondria.
Mitochondrial transfer was accompanied by changes in gene expression (activity) and other molecular findings consistent with improved energy metabolism in both the brain and heart.
These molecular changes were accompanied by broader improvements in mice. Treatment improved growth and hair loss in both male and female FA mice. In females, survival increased from 53% in pooled FA controls to 80%, and movement, coordination, muscle strength, and heart function also improved. Male mice showed a trend toward better survival, but the difference was not statistically significant.
To investigate mitochondrial transfer more directly, the researchers grew donor bone marrow-derived macrophages alongside skin fibroblasts from FA mice or from people with FA. Several methods confirmed that mitochondria moved from the macrophages into the FA fibroblasts.
The transfer required direct cell contact and appeared to occur mainly through actin-dependent structures that can form tiny bridges between neighboring cells. FA cells that received mitochondria showed partially restored respiratory capacity (ability to use oxygen to produce energy), although this remained below healthy levels.
The findings suggest myeloid cell replacement may help in two ways: by replacing dysfunctional immune cells and by providing a lasting source of healthier mitochondria that can be transferred to frataxin-deficient cells.
Still, “the degree of rescue is substantial but incomplete,” the researchers wrote. Bone marrow or hematopoietic stem cell transplant requires conditioning that carries potential risks, meaning further studies are needed before the strategy could be considered for people with FA.
Leave a comment
Fill in the required fields to post. Your email address will not be published.