In this open access paper, results are presented for an animal study of an approach to increasing the pace of remyelination in the brain. Myelin acts as sheathing for the axons that connect nerve cells; when it is degraded, insufficiently maintained, or damaged, the result is dysfunction in the nervous system. A range of demyelinating diseases result from the loss of myelin in specific locations, many of which are life-threatening. To a lesser degree, loss of myelin occurs over the course of aging for all of us. It is unclear as to the degree that this process contributes to age-related decline in cognitive and physical function, but given what is known from the observation of demyelinating diseases it is unlikely that the losses are harmless. Thus it is well worth paying attention to progress towards therapies that can increase the rate of remyelination, as it is likely that a robust and effective approach would be useful for all older individuals:
Microglia play critical but incompletely understood roles in propagation and resolution of central nervous system (CNS) injuries. These cells modulate neuroinflammation, produce factors that regulate activities of astrocytes, oligodendrocytes, and neurons, and clear debris to provide an environment for oligodendrocytes to begin to remyelinate neurons. Separately, limited information is available concerning the role of human blood monocytes in the dynamics of repair of brain injury. Circulating human monocytes include subpopulations that differ in their ability to migrate to tissues, proliferate, and form inflammatory or reparative macrophages at sites of injury. Based on experiments in rodents, several groups have proposed that cell products composed of human monocytes could be considered as candidates for the treatment of injury-induced CNS demyelination. CD14+ monocytes present in human umbilical cord blood (CB) are among these candidates.
We have recently developed DUOC-01, a cell therapy product composed of cells with characteristics of macrophages and microglia that is intended for use in the treatment of demyelinating CNS diseases. DUOC-01 is manufactured by culturing banked CB-derived mononuclear cells (MNCs). The studies described in this report were designed to provide proof of concept for the use of DUOC-01 in treatment of demyelinating diseases that do not arise from enzyme deficiency. To accomplish this, we assessed the ability of DUOC-01 to promote remyelination of mouse brain after cuprizone-induced (CPZ-induced) demyelination, a model that has been widely used to study the mechanisms and cellular dynamics of remyelination in the corpus callosum (CC) region, and also to test the effects of various interventions, including cell therapy agents.
We showed, to the best of our knowledge for the first time, that CPZ feeding in immunodeficient mice results in reversible demyelination in the CC with a time course similar to the process in immune-competent mouse strains, and that this model can be used to assess the activity of human cell therapy products in promoting brain remyelination. Using this model, we demonstrate that the DUOC-01 cell product accelerates brain remyelination following CPZ feeding. We also show that uncultured CD14+ CB cells that give rise to DUOC-01 also accelerate remyelination, but significantly less actively than DUOC-01 cells. A comparison of whole-genome expression arrays of CB CD14+ monocytes and DUOC-01 revealed large differences in gene expression, and helped identify candidate molecules that may participate in remyelination. We subsequently confirmed that cells in the DUOC-01 product express and secrete several factors that promote myelination by several mechanisms.