Research in mice by an international team of scientists in Denmark and in the United States has answered some important questions about the viability of treatments that seek to replace diseased and aged cells in the central nervous system with healthy ones. The findings have implications for a number of neurological and psychiatric disorders—including Huntington’s disease, amyotrophic lateral sclerosis (ALS), and schizophrenia—that have been linked to glia, a population of cells that support brain health and function.
The new study, headed by Steve Goldman, MD, PhD, professor of neurology and co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine, describes the ability of human glial progenitor cells (hGPCs) to compete with one another in the adult brain, and the competitive advantage of young and healthy cells over aged and diseased cells. Glial progenitor cells are precursor cells that can give rise to both astrocytes and oligodendrocytes, the two major types of glia.
“A broad variety of disorders we associate with neuronal loss now appear to be caused by dysfunctional glial cells,” said Goldman. “This makes these diseases attractive targets for stem and progenitor cell-based therapies.” Goldman is lead author of the team’s published paper in Nature Biotechnology, which is titled, “Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain,” and in which the team concluded, “These data indicate that aged and diseased human glia may be broadly replaced in the adult brain by younger healthy hGPCs, suggesting a therapeutic strategy for the replacement of aged and diseased human glia.”
Glial dysfunction contributes causally to a broad spectrum of neurological conditions, the authors wrote. “Astrocytic and oligodendrocytic pathologies have been associated with the genesis and progression of a number of both neurodegenerative and neuropsychiatric disorders, including conditions as varied as amyotrophic lateral sclerosis, Huntington’s disease (HD), and Parkinson’s disease, as well as schizophrenia and bipolar disease.” It’s feasible that for these conditions, replacing diseased glia with healthy hGPCs might offer tangible therapeutic benefits, as the hGPCs have the ability to disperse and colonize their hosts, while giving rise to new astrocytes and oligodendrocyte. However, the team continued, while it has been shown in experimental therapeutic models that human GPCs can replace mouse GPCs, “… it has remained unclear if allografted human GPCs can replace other human cells, diseased or otherwise.”
In 2013, Goldman and colleagues first reported strategies for producing the brain’s glial support cells from embryonic stem cells. In later research, the lab transplanted these cells into the brains of baby mice, resulting in the creation of human glial-chimeric mice, a technical achievement that enables the researchers to study human glial cells in the living brain. The team showed that after transplantation, the human glial progenitor cells quickly outcompeted native cells, resulting in brains with mouse neurons and human glia.
In later experiments, the lab transplanted human glial cells with the Huntington’s disease (HTT) mutation. They observed that this mutation impaired the function of glial progenitor cells, resulting in poor astrocytes and oligodendrocytes production. The lab also showed that transplanting healthy human glial progenitor cells into mouse models of Huntington’s delayed disease progression, reinforcing the important role that glial dysfunction plays in this still untreatable neurodegenerative disease. “We had previously established that glial pathology is causally involved in the synaptic dysfunction of HD and that replacement of mHTT-expressing mouse glia by implanted healthy hGPCs was sufficient to both delay disease progression and rescue important elements of function in transgenic HD mouse models,” they stated.
As these prior studies were limited to the transplant of human cells into the mouse brain, the question remained whether human cells transplanted into another human brain would yield the same type of benefit. The newly published Nature Biotechnology study strongly suggests that they can, and highlights the potential value of cell replacement therapies by showing that healthy human glia will outcompete and replace sick human cells.
To demonstrate this, the researchers first implanted human glial progenitor cells with the HTT mutation into the brains of newborn mice. “Following implantation, the HD glia rapidly infiltrated the striata of these mice, migrating and expanding first within the striatal white matter tracts and then progressively displacing their mouse counterparts from the striatal neuropil.” After the animals reached adulthood, the researchers then transplanted healthy (wild-type; WT) human glial cells. “Having established chimeras whose striatal glia were largely HTT-expressing and human, we next asked how these resident HD human glia might respond to the introduction of healthy hGPCs,” the scientists commented. They found that these human glial cells went on to displace and eliminate their Huntington’s disease counterparts. “Following engraftment, the WT glia pervaded the previously humanized striatum, gradually displacing their HD counterparts as they expanded from their implantation site. This process was slow but sustained, over time yielding substantial repopulation of the HD striatum with WT glia.”
“In the striatum, our target area, the healthy cells essentially kicked out the disease cells, eventually replacing the glial progenitor population entirely,” said Goldman. “You can actually see a wave of migration and a border where the cells expressing the HTT mutation are dying off and being replaced by healthy ones.” The authors further noted, “Remarkably, the expansion of WT glia was paralleled by a concurrent elimination of HD glia from the tissue … This was typically characterized by a discrete advancing front, behind which few HD glia could be found.”
In an accompanying set of experiments, the researchers found that younger healthy human glial progenitors outcompeted older and otherwise healthy human glia, suggesting that cellular youth is a critical determinant of competitive success. The combined results, the team suggested, “… indicated that the repopulation of the human WT glial chimeric striatum by younger isogenic hGPCs was attended by the replacement of the older cells by their younger counterparts, fueled in part by the relative expansion of the younger, more mitotically active cell population.” Their findings also indicated that “the older, resident glia were actively eliminated by the younger, introduced glia, at least partly via apoptosis, triggered by their encounter with the younger hGPCs, whose greater relative fitness permitted their repopulation of the chimeric host striatum.”
Goldman commented, “These findings have strong therapeutic implications, as they suggest that in the adult human brain, resident glia—whether diseased or simply aged—may be replaced following the introduction of younger and healthier cells.”
Noting that their studies were carried out in a model system that has inherent limitations, the authors nevertheless stated that, given the many neurodegenerative and neuropsychiatric diseases in which causally contributing glial pathology is now recognized, the clinical implications of their observation that resident healthy or diseased glia may be ousted by younger, healthier GPCs, could be profound. “… it suggests that the dysfunctional glia of diseased brains, across a variety of disease etiologies and phenotypes, might be effectively eliminated and replaced by the intracerebral delivery of newly generated allogeneic hGPCs.” And with caveats noted, the team concluded, “our results suggest that glial progenitor cell delivery and glial replacement may offer a viable and broadly applicable strategy toward the cell-based treatment of those diseases of the brain in which glial cells are causally involved.”