You may find it interesting that when people with leukaemia undergo bone marrow transplantation from a donor of the opposite sex that cells derived from the transplant can be found within the brain several years later. We know these cells are donor derived because in female recipients these cells have a Y or male chromosome. Presumably stem cells from the donor bone marrow are released and migrate into the brain and give rise to new microglia and neurones; all be the latter in small numbers.
Cogle et al. Bone marrow transdifferentiation in brain after transplantation: a retrospective study. Lancet. 2004 May 1;363(9419):1432-7.
Is this important for MS? May be it is! The reason I say this is that bone marrow derived stem cells and monocytes use the same receptor as lymphocytes to cross the blood-brain-barrier, i.e. VLA4. Interestingly and importantly, this is the receptor that is blocked by natalizumab. Natalizumab will therefore block the migration of bone-marrow derived stem cells into the brain and spinal cord.
Is this dangerous? In the short-term it appears not to be as MSers do very well on natalizumab. But I am worried about the long term effects of natalizumab on bone-marrow derived stem cell and monocyte migration; do our brains and spinal cord lose their ability to repair themselves if they are cut-off from these sources of cells? If they do, natalizumab-treated MSers may be at risk of premature ageing.
Question: Do MSers on long-term natalizumab treatment, i.e. greater than 10 years or more, develop premature ageing of the brain due to the loss of trophic support from bone-marrow-derived stem cells?
To answer this question we need long-term monitoring of natalizumab-treated MSers to look for markers of premature ageing, i.e. the premature development of age-related neurodegenerative disorders, for example Alzheimer's, Parkinson's or other age-related neurodegenerative diseases. This adverse event would take decades to emerge; therefore we need to remain vigilant for unexpected biological consequences of reducing trafficking of stem and other cells into the brain and spinal cord.
Why is this a grand challenge? Simply because so many MSers are now on natalizumab and the first MSers treated are getting to the time window when these potential effects would start emerging. And it is something that keeps me awake at night!
Clues to support my anxieties come from the conjoined mice or parabiosis experiments we have posted on before on this blog:
These experiments show that the ageing brain in older mice responded to something from the circulation of younger mice; the factor seemed to be chemical signals that promote cellular migration across the blood brain barrier. It would be interesting to see what would happen in the conjoined twin or parabiosis experiment if the mice were treated simultaneously with mouse natalizumab; i.e. would mouse natalizumab block the brain regenerative effects of youth in the older mice?
If you are on natalizumab and develop new or unexplained symptoms, that you think may or may not be related to MS, let your MS team know.
Labels: Grand Challenges, Natalizumab, Stem Cells