First, targeting of mature OLs without off-targets on the immature stages of the OL lineage may be important, given their differential susceptibilities to injury and responses to extrinsic factors. Although mature OLs were long considered not to contribute to remyelination, recent work has surprisingly demonstrated the contrary. Studies have demonstrably shown that OLs surviving demyelination can extend processes to remyelinate, as shown in cats, mouse, and zebrafish188–190. Consistent with these findings, 14C-labeling suggests that remyelinating MS lesions contain ‘old’ OLs191, implying that existing OLs mediated remyelination (although non-proliferating OPC-derived OLs may have also contributed). However, in an elegant study performed in zebrafish larvae enabling imaging of OL behavior in real time, Neely et al. revealed that OLs surviving demyelination remyelinate poorly compared to newly generated OLs, extending fewer processes and mistargeting myelin to neuronal cell bodies190; importantly, this mistargeted myelin profile was also found in MS lesions190. These studies suggest that therapeutic targeting of OL survival would need to also take into account the potential for ensuing poor quality remyelination. Revealing the mechanisms underpinning surviving OL-mediated remyelination, and how this
