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Immunomodulatory Function of NPCs Improves Recovery in Animal Model of Multiple Sclerosis

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Review of “Subcutaneous Transplantation of Neural Precursor Cells in Experimental Autoimmune Encephalomyelitis Reduces Chemotactic Signals in the Central Nervous System” from Stem Cells Translational Medicine by Stuart P. Atkinson

Multiple sclerosis (MS) is caused by autoreactive T-cells entering the central nervous system (CNS – brain and spinal cord) and attacking the myelin sheaths which surround neurons (1). This leads to loss of function and death of affected neurons, although neural progenitor cells (NPCs) may represent an effective treatment for this loss, due to their ability to differentiate to oligodendrocytes to remyelinate axons after transplantation [1, 2]. However, recent studies have suggested that NPCs may also have a positive influence on the immune environment [3, 4].

Now, in a new study in Stem Cells Translational Medicine, researchers from the laboratory of Nikolaos Grigoriadis (AHEPA University Hospital, Greece) have explored this immunomodulatory role in an animal model of MS (experimental autoimmune encephalomyelitis - EAE). They have discovered that transplantation of NPCs outside of the CNS improves recovery through the modification of chemokine signaling within the CNS and the impaired recruitment of damaging immune cells [5].

Following subcutaneous injection into the hind limb flanks of mice after EAE induction, the authors observed little migration or differentiation of NPCs. However, NPC transplantation still significantly ameliorated the clinical severity of EAE (See Figure), delayed disease onset, and reduced both demyelination and neuron dysfunction. The study linked these improvements to a reduction in the number of infiltrating T-cells and monocytes into the spinal cord, and, additionally, to a reduction in the level of astrogliosis (an abnormal increase in the number of astrocytes due to the destruction of nearby neurons) and in the number of microglia (resident macrophages).

So how did NPC transplantation in a distant site affect immune cell infiltration? Gene expression analysis of the CNS demonstrated that NPCs reduced CNS levels of several T cell-recruiting chemokines and their receptors, so leading to the reduction in immune cell infiltration observed, and the improved recovery.

This extends what we understand about the immunomodulatory functions of NPCs in neuroinflammatory disorders, and the authors note that this may lead to the faster translation of NPCs into potential clinical use. Looking to the future, harnessing both the NPC-mediated downregulation of the chemotactic signals expressed by the inflamed CNS and the ability of NPCs to promote remyelination through differentiation to oligodendrocytes could lead to a synergistic effect and boost our efforts to treat human MS patients.

References

  1. Nait-Oumesmar B, Decker L, Lachapelle F, et al. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci 1999;11:4357-4366.
  2. Picard-Riera N, Decker L, Delarasse C, et al. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc Natl Acad Sci U S A 2002;99:13211-13216.
  3. Ben-Hur T Immunomodulation by neural stem cells. J Neurol Sci 2008;265:102-104.
  4. Einstein O, Fainstein N, Vaknin I, et al. Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol 2007;61:209-218.
  5. Ravanidis S, Poulatsidou KN, Lagoudaki R, et al. Subcutaneous Transplantation of Neural Precursor Cells in Experimental Autoimmune Encephalomyelitis Reduces Chemotactic Signals in the Central Nervous System. Stem Cells Transl Med 2015;4:1450-1462.