Date: 27th April 2021
Dementia is one of the leading causes of death globally, with the two most common causes being Alzheimer’s disease and white matter stroke (WMS). WMS occurs in the deep penetrating blood vessels in the brain, and are small strokes that typically go unnoticed but accumulate over time. This debilitating disorder leads to cognitive and motor impairments, and currently there are no therapies that enhances the brain’s own ability to recover from this disease or prevent the expansion of WMS over time. Now, researchers identify an new glial cell therapy that halts the progressive damage caused by the WMS and stimulates the brain’s own repair processes.
The two leading causes of dementia, Alzheimer’s and WMS, are almost always seen together and one accelerates the others. WMS damages different cellular constituents in the brain such as astrocytes, axons, oligodendrocytes, and myelin, and as such it has been a challenge to develop treatments such as gene therapies or cell transplant therapies that lead to neural repair. The expansion of WMS is associated with degeneration of partially demyelinated axons, and it has been thought that the ability to repair such damage may provide beneficial effects on the survival of axons adjacent to WMS and prevent lesion expansion.
Now, scientists led by Thomas Carmichael and William Lowry, at University of California, Los Angeles, UCLA, have used a mouse model of WMS to show that transplantation of glial enriched progenitor cells shortly after a stroke, mature into astrocytes with a prorepair phenotype. They had a therapeutic effect on axonal damage, induced remyelination, and promoted axonal sprouting furthermore, this led to enhanced motor and cognitive recovery.
The team hypothesised that an astrocytic therapy would be a good target for brain repair after WMS, as immature astrocytes promote oligodendrocyte progenitor cell (OPC) differentiation and myelination. To start the researchers created the glial enriched progenitors (GEP) cells which were differentiation from human-induced pluripotent stem cells, and termed hiPSC-GEPs. They were induced using an experimental hypoxia manipulation which drove the bias of these cells to further differentiate into an astrocyte fate. These were then injected into the brains of WMS-modelled mice after stroke induction, which recapitulated early to middle stages of human dementia.
The hiPSC-GEPs transplanted after subcortical white matter stroke, migrated widely to the contralateral white matter, striatum and cortex, migrating out of the injection area. The cells were able to proliferate, and created progenitors that were astrocyte-like and associated with vessels in a similar fashion to endogenous brain astrocytes. A reduction in infarct size was observed, as was an increase in fiber tract and axonal projections density. In addition, the myelin around the infarct site showed greater integrity and was associated with an increase in the cells with markers of mature oligodendrocytes – cells which create the myelin sheath.
Whilst, these data showed encouraging signs of repair to the brain, the team wanted to assess whether this was accompanied by functional recovery. Here, they saw a significant improvement in motor control over time. Interestingly, depletion of the transplanted cells via diphtheria toxin (DT) 4 months after stroke did not deplete the motor control recovery, this suggested that the transplanted hiPSC-GEPs induced a local repair response and recovery of motor control, and once the recovery was in place the cells were no longer needed. Further work showed that cognitive performance was also improved.
Conclusions and future applications
The work here has demonstrated that this unique glial repair stem cell therapy for the treatment of common and progressive strokes and dementia can stimulate white matter repair, which was accompanied by improvements in motor and cognitive performance.
The team plan to test the therapy for safety and efficacy through clinical trials. They see the therapy as an off-the-shelf product. As the brain is immune privilege, meaning that immune activity is highly controlled, it is particularly amenable to therapies which would be rejected by other regions of the body. As time to treatment is crucial for strokes, personalised therapies from harvesting patients own cells would be too lengthy, and ready to go therapies would be hugely beneficial for these patients.
In the near future, the team will be examining the effects of hiPSC-GEP transplantation in aged animals as they more closely mimic human patients, distinct time points, and sites of injection (such as near the stroke versus into distant sites) and different doses. The experiments performed here were on immunocompromised mice, which aided human cell engraftment and minimised rejection in mice however, this might alter the endogenous response which will be investigated further.
From a wider perspective the ability to regenerate myelin would benefit other diseases. We have recently seen the development of gene therapy carrying therapeutic shRNAs which facilitated remyelination of peripheral nerves caused by the genetic Charcot-Marie-Tooth disease (CMT). This was also accompanied by prevention of motor and sensory impairments. Together these works promote the use of therapies that are able to repair damaged myelin by either stimulating the body’s own repair systems or by targeting the therapy to the cells that deposit myelin (such as Schwann cells in the case of CMT). It is hoped that these types of novel treatments, which may need to be considered in combination depending on which cells are affected, the type of the disease or which part of the nervous system is damaged, will change the way we treat demyelinating diseases, strokes and dementia in the future.
For more information please see the press release from UCLA
Llorente, I.L., Xie, Y., Mazzitelli, J.A., Hatanaka, E.A., Cinkornpumin, J., Miller, D.R., Lin, Y., Lowry, W.E., and Carmichael, S.T. (2021). Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents. Science Translational Medicine 13, eaaz6747.
https://doi.org/10.1126/scitranslmed.aaz6747
