Remyelination is a hot topic
In the paper below they say
“The view that differentiation of OPC into mature myelinating oligodendrocytes is required for successful remyelination in humans has been challenged recently. Measuring the integration of 14C derived from nuclear testing into DNA of oligodendroglial lineage cells Yeung et al. suggest that pre-existing oligodendrocytes and not proliferating OPC may contribute to remyelination in MS. Moreover, Jäkel et al. performed scRNA-seq analysis and identified different subpopulations of OPC and oligodendrocytes in brain tissue samples from MS patients and healthy individuals which only partly overlapped with oligodendroglial subsets identified in mouse brains. They propose that the loss of certain subpopulations and the skewing of the differentiation program to other subclasses of mature oligodendrocytes contribute to impaired remyelination in MS.
So the view was to para-phrase that the mousers have been wasting their time, but their (the mousers) response to this was to suggest that pathologists are essentially “useless”, and the tissues (shadow plaques) analysed in the above studies were not remyelination. The response by the pathologists has so far been non existent and suggests that they don’t mind being called “useless”. I have been frankly shocked by the responses to these questions by some people (pathologists) . This is a essential aspect of MS pathology. We need consensus
Lesion stage-dependent causes for impaired remyelination in MS.Heß K, Starost L, Kieran NW, Thomas C, Vincenten MCJ, Antel J, Martino G, Huitinga I, Healy L, Kuhlmann T.Acta Neuropathol. 2020 Jul 24. doi: 10.1007/s00401-020-02189-9
Multiple sclerosis (MS) is the most frequent demyelinating disease and a leading cause for disability in young adults. Despite significant advances in immunotherapies in recent years, disease progression still cannot be prevented. Remyelination, meaning the formation of new myelin sheaths after a demyelinating event, can fail in MS lesions. Impaired differentiation of progenitor cells into myelinating oligodendrocytes may contribute to remyelination failure and, therefore, the development of pharmacological approaches which promote oligodendroglial differentiation and by that remyelination, represents a promising new treatment approach. However, this generally accepted concept has been challenged recently. To further understand mechanisms contributing to remyelination failure in MS, we combined detailed histological analyses assessing oligodendroglial cell numbers, presence of remyelination as well as the inflammatory environment in different MS lesion types in white matter with in vitro experiments using induced-pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) and supernatants from polarized human microglia. Our findings suggest that there are multiple reasons for remyelination failure in MS which are dependent on lesion stage. These include lack of myelin sheath formation despite the presence of mature oligodendrocytes in a subset of active lesions as well as oligodendroglial loss and a hostile tissue environment in mixed active/inactive lesions. Therefore, we conclude that better in vivo and in vitro models which mimic the pathological hallmarks of the different MS lesion types are required for the successful development of remyelination promoting drugs.
There is a lot in this and I am glad we (MDs) have not put too much energy into experimental remyelination studies, but a lot of effort and resource has. I am sitting on the side-lines watching this unfold, thinking surely the questions posed here are so fundemental that we need answers
The conclusions of this current study are disappointing
They say “pharmacological approaches that focus exclusively on promotion of oligodendroglial differentiation to enhance remyelination might fail“, treatment strategies targeting multiple of the steps required for successful remyelination, namely oligodendroglial proliferation, migration, differentiation, myelin sheath formation, and survival should be considered. Our data also suggest that promotion of remyelination in progressive MS in which mixed and inactive lesions dominate may require different treatment approaches compared to RRMS characterized by more active lesions. “
This is not what you want to hear and trials have been planned on the idea of a maturation failure of OPC…Should they be put on hold?.
The Mousrs/Ratters need to respond to this one.
The MS Societies better get the pathologists together to get some consensus PDQ (pretty dammed quick) because if this can’t be done then we will start to say we can’t believe anything that these people are saying and have said in the past.
Having seen two present the opposite story with 5 minutes of each other and neither questions the other quite recently says either they don’t believe their own work or are frightened of the confrontation, but they have critized animal studies when it suites them and and used the same models subsequently, makes me concerned.
Surely there is no point in making new models unless you can agree what to model. As for new models, essentially none of the current models examine anything, but a acute demyelinating event that repairs without doing anything. Then we use that to justify a study where we think chronic demyelination with gliosis is present. If the study doesn’t work we blame the animal models rather than the scientists for not doing a translatable experiment.
COI: None relevant