Cell Fusion along the Anterior-Posterior Neuroaxis in Mice with Experimental Autoimmune Encephalomyelitis.

BACKGROUND: It is well documented that bone marrow-derived cells can fuse with a diverse range of cells, including brain cells, under normal or pathological conditions. Inflammation leads to robust fusion of bone marrow-derived cells with Purkinje cells and the formation of binucleate heterokaryons in the cerebellum. Heterokaryons form through the fusion of two developmentally differential cells and as a result contain two distinct nuclei without subsequent nuclear or chromosome loss. AIM: In the brain, fusion of bone marrow-derived cells appears to be restricted to the complex and large Purkinje cells, raising the question whether the size of the recipient cell is important for cell fusion in the central nervous system. Purkinje cells are among the largest neurons in the central nervous system and accordingly can harbor two nuclei. RESULTS: Using a well-characterized model for heterokaryon formation in the cerebellum (experimental autoimmune encephalomyelitis - a mouse model of multiple sclerosis), we report for the first time that green fluorescent protein-labeled bone marrow-derived cells can fuse and form heterokaryons with spinal cord motor neurons. These spinal cord heterokaryons are predominantly located in or adjacent to an active or previously active inflammation site, demonstrating that inflammation and infiltration of immune cells are key for cell fusion in the central nervous system. While some motor neurons were found to contain two nuclei, co-expressing green fluorescent protein and the neuronal marker, neuron-specific nuclear protein, a number of small interneurons also co-expressed green fluorescent protein and the neuronal marker, neuron-specific nuclear protein. These small heterokaryons were scattered in the gray matter of the spinal cord. CONCLUSION: This novel finding expands the repertoire of neurons that can form heterokaryons with bone marrow-derived cells in the central nervous system, albeit in low numbers, possibly leading to a novel therapy for spinal cord motor neurons or other neurons that are compromised in the central nervous system.

Oxidative stress increases neurogenesis and oligodendrogenesis in adult neural progenitor cells.

Hydrogen peroxide (H2O2) is a reactive oxygen species that is involved in immunity and neuroinflammation. Here, we investigated whether and how pathophysiological levels of H2O2 influenced the differentiation of neural progenitor cells (NPCs). H2O2 levels within the range measured at neuroinflammatory events were applied to rat primary NPC cultures during 24 h, and effects were assessed directly after exposure or in NPCs that were differentiated for 7 days after H2O2 removal. Exposed differentiated NPCs showed significantly increased numbers of neurons and oligodendrocytes compared with unexposed controls. To identify the possible origin of this differentiation result, we characterized the undifferentiated culture and found a significant increase in both OLIG2(+) cells and proliferative ASCL1(+) C cells that could contribute to both more neurons and oligodendrocytes. In addition, H2O2-induced neurogenesis was supported by western blot and paralleled by gene expression analyses, which revealed an increased expression of the proneural gene Ngn2 and the neuronally expressed gene ß-III tubulin. To investigate potential mechanisms for the observed effects on NPC differentiation, we performed gene expression profile analyses for oxidative stress and antioxidant-related and chromatin modification genes where the expression of several important genes was affected by the exposure. Increased oligodendrocyte numbers correlated with increased expression of the chromatin modification enzyme Sirt2, suggesting the involvement of Sirt2 in oligodendrocyte differentiation. Our results suggest a modulatory effect on the differentiation potential of NPCs by H2O2. Our findings indicate that H2O2 exposure has significant effects on NPC proliferation, differentiation, and vulnerability. These results have implications for regeneration after any neuroinflammatory event.