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Fate mapping of precursor cells following CNS demyelination

Final Activity Report Summary - FMPCD (Fate mapping of precursor cells following CNS demyelination)

One of the most exciting developments in biomedical sciences in recent years has been the realisation that the adult CNS contains an abundant and widespread population of precursor cells called oligodendrocyte precursor cells (OPCs) that can be mobilised in response to damage and mediate regeneration. The best example of CNS regeneration is remyelination, a highly efficient process in which demyelinated axons (axons which lost the myelin sheaths as a consequence of oligodendrocyte damage) are reinvested with new myelin and pre-lesion architecture and function are restored.

A better understanding of the molecular mechanisms controlling diversity and differentiation of brain adult OPCs are necessary to develop endogenous strategies for clinical remyelination enhancement by activating precursor cells and modulating their differentiation ability. The existing evidence that these cells are the major source of remyelinating oligodendrocytes is compelling but indirect: there has never been a formal demonstration using lineage tracing strategies that they give rise to remyelinating oligodendrocytes. To establish the differentiation fates of endogenous precursor cells responding to CNS white matter demyelination we have performed experiments using a well-defined mice model of toxin-induced primary demyelination/remyelination in the CNS to. The cre-lox technology employed in this project is at the leading edge of technologies used to study the regenerative biology of adult CNS precursors.

Our data provided the first unequivocal evidence on the relationship between precursor cells responding to demyelination and the differentiated phenotypes contributing to the reconstruction of the damaged tissue. These cells exhibit more stem cell-like features than previously recognised, giving rise to oligodendrocytes as well as astrocytes or even Schwann cells (the myelinating cells of the peripheral nervous system that can remyelinate CNS axons) in response to demyelination. It may therefore be appropriate to abandon the term OPC in favour of glial precursor/progenitor cell or even neural precursor/progenitor cell, terms that better reflect their differentiation potential. This data are not only being of considerable scientific interest but will also have profound implications for the understanding of remyelination and how it can be harnessed therapeutically.