Stem cell transplant alters immune cells in MS mouse model: Study
Myeloid cell replacement could help with chronic inflammation
A stem cell transplant effectively reduced the abnormal immune response that drives multiple sclerosis (MS) progression by altering a specific group of immune cells called myeloid cells, a mouse study showed.
Treatment with a compound that suppressed a receptor called CSF1R improved the transplantation efficiency of myeloid cells and further boosted their neuroprotective effects.
“These data suggest that myeloid cell manipulation or replacement may be an effective therapeutic strategy for chronic inflammatory conditions of the [brain and spinal cord],” the researchers wrote.
The study, “Myeloid cell replacement is neuroprotective in chronic experimental autoimmune encephalomyelitis,” was published in the journal Nature Neuroscience.
MS is an autoimmune disease in which the immune system mistakenly attacks the insulating cover around nerve fibers, called the myelin sheath, in the brain and spinal cord. Such attacks disrupt the transmission of nerve signals, resulting in a range of MS symptoms.
Transplant has potential to slow disease, but mechanism isn’t clear
Autologous hematopoietic stem cell transplant (aHSCT), more simply called stem cell transplant, is a potential treatment option for MS patients with very active disease who have not responded well to disease-modifying therapies).
The treatment involves collecting hematopoietic stem cells, or those that give rise to blood cells, from a patient’s bone marrow or blood. After depleting the immune system with chemotherapy, the stem cells are returned to the same patient (autologous) with the goal of resetting the immune system to a healthy state.
Despite evidence demonstrating its potential to slow disease progression in people with active MS, it’s unclear exactly how aHSCT resets the immune system, particularly during the late, chronic stages of MS.
Scientists at the Stanford University School of Medicine applied a technique called RNA sequencing to create a snapshot of the gene activity in immune cells, before and after a stem cell transplant. They did this analysis in mice with experimental autoimmune encephalomyelitis, a commonly used MS mouse model.
Compared with control animals, MS mice showed a marked increase in two immune cell types called myeloid cells and lymphocytes in their brains and a decrease in supportive cells, such as astrocytes and oligodendrocytes.
The induction of MS in mice resulted in marked changes in gene expression across multiple cell types, but myeloid cells showed the highest number of genes whose activity was altered by MS.
The team then confirmed that these gene activity changes in MS mice matched similar genetic changes associated with MS in patients, particularly in chronic active lesions, or areas of damage in the brain.
After transplanting stem cells into the bloodstreams of MS mice, researchers examined how different cell types changed in the brain and spinal cord. While there was robust production of myeloid cells from the transplanted stem cells, only a small proportion of these cells, referred to as circulation-derived myeloid cells (CDMCs), reached the nervous system.
However, treatment with a compound called PLX5622 after transplantation, which inhibited the CSF1R receptor, significantly increased the number of CDMCs in the brain and spinal cord.
Notably, the MS-induced increase in myeloid cell density was normalized after stem cell transplant. Moreover, transplanted myeloid cells showed global changes, but there were also changes in the distribution and structure of pre-existing microglia.
Clinical improvements were seen soon after the transplant, which was associated with reduced activity of MS-related genes in oligodendrocytes and astrocytes but increased activity in myeloid cells. These changes were further boosted with CSF1R suppression, suggesting a protective role of the myeloid response in the chronic MS model, the team noted.
Transplant combined with CSF1R suppression
Functional improvements in treated MS mice were accompanied by increased myelination and greater neuroprotective gene activity. Treatment also reduced reactive astrogliosis, an abnormal increase in the number of astrocytes due to the damage of nearby nerve cells. These benefits were more prominent when transplantation was followed by CSF1R inhibition.
The stem cell transplant not only reduced the overall number of immune cells in MS mice, but also led to changes in the composition of immune cell subtypes.
Lymphocytes trended toward normalization, while myeloid cells demonstrated increased variability, which centered around a rise in CDMC cells. Transplantation also shifted T-cells in the brain and spinal cord from a pro-inflammatory state toward a more immunosuppressive state.
Transplant-altered gene activity profiles in spinal cord myeloid cells also showed an increase in pathways linked to immune regulation, cell signaling, and debris clearance. Further experiments confirmed that CDMCs mainly drove changes in myeloid variability and associated gene activity.
“Our findings identify manipulation of the myeloid niche as a therapeutic direction for inflammatory demyelinating disease,” the scientists wrote. “Our data supports the notion that the combination of CSF1R inhibition with AHCT might have translational implications.”
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