Mesenchymal stem cells lower neurofilament levels in progressive MS

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You would have heard about HSCT for MS, but Mesenchymal stem cells (MSC) are a very different type of treatment and less well known than HSCT. In fact, I would go so far as to say that interest in this therapeutic option is almost non-existent. However, when I came across a recently published biomarker paper on this topic I thought it would be interesting to have another look at it.

Further information on the original clinical trial can be found here: https://pubmed.ncbi.nlm.nih.gov/33253391/

Mesenchymal stem cells are what are termed non-haematopoietic stromal cells because they don’t produce blood cells (red or white cells), but still reside mainly in the bone marrow where they support blood cell production. They are also reported as being able to regulate immune activation and encouraging neuronal growth. For instance, both I.V. and intrathecal administration (into the spinal compartment) of MSCs have been shown to have an anti-inflammatory effect on an animal model of MS, the EAE.

Figure: Mesenchymal stem cells (source: eurostemcell.org)

In analysis of biomarkers, a group from Israel demonstrate that particularly neurofilament light chain levels are significantly reduced in the intrathecally (or when injected directly into the spinal compartment) treated MSC group at 6 months when compared to levels at start of treatment (see Figure below).

The mean reduction was −14 723 pg/mL in the MSC-IT-treated group, −3801 pg/mL in the MSC-IV group (P = .955), and +10 905 pg/mL (increase) in the placebo group (P = .048)

They also studied a second biomarker, CXCL13 a potent attractor of B-cells and found similar reductions in this (see Figure below).

Figure: CSF levels of NF-L (A) and CXCL13 (B) at baseline and 6 months following intrathecal (MSC-IT) or intravenous (MSC-IV) treatment with MSC. Sham is the placebo group.

Although at first glance the results seem very promising, I’m drawing your attention to the very small sample sizes in all three groups. Moreover, the participants in the study appear to be very highly active MS as depicted by their baseline NfL levels and may demonstrate very wide fluctuations in their NfL levels as would be expected in those with a highly active disease course. If you add small sample size to this, the changes observed (whether up or down) may very well have occurred by chance alone. In addition, in biochemistry, there is such a thing as regression to the mean; where very high biochemical results given time eventually come down.

But, not to be completely negative about this study, I believe that it is worth exploring further in a larger Phase II study. Other remyelination trials have had lesser positive indicators than this one.


Effects of Mesenchymal Stem Cell Transplantation on Cerebrospinal Fluid Biomarkers in Progressive Multiple Sclerosis
Stem Cells Transl Med. 2022 Mar 3;11(1):55-58. 

Panayiota Petrou  Ibrahim Kassis  Ariel Ginzberg Michelle Hallimi Dimitrios Karussis 


Background: Neurofilament light chains (NF-L) were shown to serve as a reliable biomarker of neurodegeneration in multiple sclerosis (MS). The chemokine receptor CXCL13 was shown to correlate with CNS inflammatory activity and to predict the future progression of MS.

Objective: To evaluate the levels of NF-L and CXCL13 in the cerebrospinal fluid (CSF) following treatment with mesenchymal stem cells (MSC) in patients with progressive MS.

Methods: The CSF samples were obtained from 48 patients with progressive MS who participated in a double-blind randomized phase II clinical trial that tested the effects of intrathecal (IT) or intravenous (IV) transplantation of mesenchymal stem cells (MSC), at baseline (before the first injection of the MSC) and at 6 months following treatment with MSC, or sham treatment. The CSF specimens were tested in a blinded way, using a single-molecule array (SIMOA) technique.

Findings: The CSF levels of NF-L were significantly lower at 6 months following treatment with MSC-IT when compared with the baseline, pre-treatment measurements (P = .026, Wilcoxon paired test). Nine out of 15 tested patients in the MSC-IT group had a reduction in NF-L levels of more than 50% (median decrease: -4449 pg/mL) when compared with 5/15 in the MSC-IV group (median decrease: -151 pg/mL) and 1/15 in the placebo group (median increase: +2450 pg/mL) (P = .001 for MSC-IT vs. placebo, chi-square test). CXCL13 levels were also reduced at 6 months following MSC-IT treatment but not to a statistically significant level.

Conclusions: Our findings indicate possible neuroprotective effects of MSC transplantation in patients with MS.

About the author

Neuro Doc Gnanapavan

12 comments

  • Doesn’t Barts recognize elevated neurofilament light levels as evidence of active disease and thus offer proven anti-inflammatories like cladribine? Anyone with elevated sNfL should benefit from any anti-inflammatory. I guess I’m confused about why this study would indicate that MSCs are any more neuroprotective than the existing therapies.

    • We do strongly encourage NfL levels to be monitored as a marker of active disease – which is why I have stated this on the explanation. CSF NfL levels in active disease remain up for 100 days approx. from a relapse event and serum NfL levels approx 3 months and it is possible in those with highly active disease that you will when you do the sampling at 6 months catch them in the remission phase by chance alone especially when the sample size is low. This is very different to how we propose that sNFL is used in the individual with frequent monitoring to catch individual variability and relapses.

  • I remember reading on TheMS Blog a reader from the US did MSC operation in Isreal and had no impact on his MS. And was reading from different sources with similar results. Are there any differences between how they develop MSC or signal MSC for immune modulation? Would intrathecal make a difference?

    • No the selection protocol is similar for MSC from the bone marrow. Standardization of the treatment, however, has proven to be difficult. There is a hint from this data that intrathecal seems to be better but a larger sample size study needs to be done.

      • It is thought that IV route is purely immunosuppressive, whereas delivering closer to the brain/spinal cord not only immunosuppressive but may have neuroprotective effects.

  • I’ve kept my eye on Mesenchymal Stem Cells now for a while and I wonder why there isn’t a phase II trial already on the way? What’s the push back? I also paid to have my first born umbilical cord stored as this is a rich source of Mesenchymal Stem Cells in the hope that something, maybe down the line would come of it.

    • Standardisation and being produced in large quantities to be used in many individuals. The largest clinical trial I remember (presented at ECTRIMS a few years back) had ~ 200 patients over 6 years that used MSC from the patient with good outcome, but others have been small studies and inconclusive. Realistically at least one Phase 3 and other well conducted Phase 2 studies are needed for regulatory approval. Because of the production issues and their survival production will always be suboptimal.

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