UCLA researchers report that a one-time injection of an experimental stem cell therapy can repair brain damage and improve memory function in mice with conditions that replicate human strokes and dementia. The team published its study “Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents” in Science Translational Medicine.
“Subcortical white matter stroke (WMS) accounts for up to 30% of all stroke events. WMS damages primarily astrocytes, axons, oligodendrocytes, and myelin. We hypothesized that a therapeutic intervention targeting astrocytes would be ideally suited for brain repair after WMS. We characterize the cellular properties and in vivo tissue repair activity of glial enriched progenitor (GEP) cells differentiated from human-induced pluripotent stem cells, termed hiPSC-derived GEPs (hiPSC-GEPs),” write the investigators.
“hiPSC-GEPs are derived from hiPSC–neural progenitor cells via an experimental manipulation of hypoxia inducible factor activity by brief treatment with a prolyl hydroxylase inhibitor, deferoxamine. This treatment permanently biases these cells to further differentiate toward an astrocyte fate. hiPSC-GEPs transplanted into the brain in the subacute period after WMS in mice migrated widely, matured into astrocytes with a prorepair phenotype, induced endogenous oligodendrocyte precursor proliferation and remyelination, and promoted axonal sprouting. hiPSC-GEPs enhanced motor and cognitive recovery compared to other hiPSC-differentiated cell types.
“This approach establishes an hiPSC-derived product with easy scale-up capabilities that might be effective for treating WMS.”
The two most common causes of dementia are Alzheimer’s disease and white matter strokes (small strokes that accumulate in the connecting areas of the brain).
“It’s a vicious cycle: The two leading causes of dementia are almost always seen together and each one accelerates the other,” said S. Thomas Carmichael, MD, PhD, senior author of the study and interim director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.
An estimated five million Americans have dementia. “And with the aging population, that number is going to skyrocket,” noted Carmichael.
Currently, there are no therapies capable of stopping the progression of white matter strokes or enhancing the brain’s limited ability to repair itself after they occur. The new study identifies a cell therapy that can stop the progressive damage caused by the disease and stimulate the brain’s own repair processes.
The cells used in the therapy are a specialized type of glial cells. Carmichael and his collaborators evaluated the effects of their glial cell therapy by injecting it into the brains of mice with brain damage similar to that seen in humans in the early to middle stages of dementia.
“Upon injection, our cell therapy traveled to damaged areas of the brain and secreted chemicals called growth factors that stimulated the brain’s stem cells to launch a repair response,” said Irene Llorente, PhD, the paper’s first author and an assistant research professor of neurology at the David Geffen School of Medicine at UCLA.
Activating that repair process not only limited the progression of damage, but it also enhanced the formation of new neural connections and increased the production of myelin.
“Understanding the role that glia play in repairing white matter damage is a critically important area of research that needs to be explored,” said Francesca Bosetti, a program director at the National Institutes of Health’s National Institute of Neurological Disorders and Stroke, which supported the study. “These preliminary results suggest that glial cell-based therapies may one day help combat the white matter damage that many stroke and vascular dementia patients suffer every year.”
In the future, if the therapy is shown to be safe and effective through clinical trials in humans, the researchers envision it becoming an “off-the-shelf” product, meaning that the cells would be mass manufactured, frozen and shipped to hospitals, where they could be used as a one-time therapy for people with early signs of white matter stroke.