Abstract
Background & Aim We have developed DUOC-01, a cord-blood derived, macrophage-based cell therapy product to treat demyelinating conditions of the central nervous system. Previously, we demonstrated that DUOC-01 accelerated remyelination, decreased gliosis, and reduced cellular infiltration in the corpus callosum of immune-incompetent mice treated with cuprizone. To explore the mechanism of action and investigate whether DUOC-01 will be effective in other experimental models of demyelination, we tested DUOC-01 in lysophosphatidylcholine (LPC) mediated demyelinated murine organotypic cerebellar brain slices and a mouse model of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). EAE has been recognized as the most widely used animal models to study the underlying molecular mechanisms of MS and the efficacy of potential therapeutics for treatment of disease. Methods, Results & Conclusion First, in the LPC-mediated demyelinated cerebellar brain slices, we found that DUOC-01 treatment increased remyelination, decreased gliosis, and promoted the proliferation of oligodendrocyte progenitor cells compared to the untreated control samples. EAE was induced in C57BL/6 mice by immunizing with myelin oligodendrocyte glycoprotein (MOG). After 10-12 days of EAE induction, when animals started showing early disease symptoms, we administered 3 × 105 DUOC-01 cells into the cerebrospinal fluid by a single intra-cisterna magna injection and clinical score was recorded for next several days. Compared to the vehicle injected control mice (n=9), in DUOC-01 treated mice (n=9), we observed significantly decreased severity of the disease as soon as the treatment started, as indicated by lower clinical scores based on motor dysfunction or severity of ascending paralysis. Histological analysis of lumber region of the spinal cord tissues from EAE mice revealed reduced inflammation and lower cellular infiltration in DUOC-01 treated samples compared to the vehicle injected controls. Presently we are analyzing single cell sequencing data to determine various sub-populations present in DUOC-01 cultures and to understand the functional pathways responsible for promoting remyelination and lowering neuroinflammation. In brief, our data suggest that DUOC-01 cell therapy product could be beneficial in treating MS and other diverse neurological conditions with demyelination.
Published Version
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