Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

J. P. J. M. de Munter, J. Mey, T. Strekalova, B. W. Kramer, E. Ch. Wolters*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

2 Citations (Web of Science)

Abstract

Neurodegenerative disorders share the final degenerative pathway, the inflammation-induced apoptosis and/or necrosis, irrespective of their etiology, be it of acute and chronic traumatic, vascular and idiopathic origin. Although disease-modifying strategies are an unmet need in these disorders, lately, (pre)clinical studies suggested favorable effects after an intervention with bone marrow-derived stromal cells (bm-SC). Recent interventions with intrathecal transplantation of these cells in preclinical rodent models improved the functional outcome and reduced the inflammation, but not anti-inflammatory drugs. The benefit of bm-SCs was demonstrated in rats with an acute (traumatic spinal cord injury, tSCI) and in mice with a chronic [amyotrophic lateral sclerosis (ALS)-like FUS 1-358 or SOD1-G93-A mutation] neurodegenerative process. Bm-SCs, were found to modify underlying disease processes, to reduce final clinical SCI-related outcome, and to slow down ALS-like clinical progression. After double-blind interventions with bm-SC transplantations, Vehicle (placebo), and (non)steroidal anti-inflammatory drugs (Methylprednisolone, Riluzole, Celecoxib), clinical, histological and histochemical findings, serum/spinal cytokines, markers for spinal microglial activation inclusive, evidenced the cell-to-cell action of bm-SCs in both otherwise healthy and immune-deficient tSCI-rats, as well as wild-type and FUS/SOD1-transgenic ALS-like mice. The multi-pathway hypothesis of the cell-to-cell action of bmSCs, presumably using extracellular vesicles (EVs) as carriers of messages in the form of RNAs, DNA, proteins, and lipids rather than influencing a single inflammatory pathway, could be justified by the reported differences of cytokines and other chemokines in the serum and spinal tissue. The mode of action of bm-SCs is hypothesized to be associated with its dedicated adjustment of the pro-apoptotic glycogen synthase kinase-3 beta level towards an anti-apoptotic level whereas their multi-pathway hypothesis seems to be confirmed by the decreased levels of the pro-inflammatory interleukin (IL)-1 beta and tumor necrosis factor (TNF) as well as the level of the marker of activated microglia, ionized calcium binding adapter (Iba)-1 level.

Original languageEnglish
Pages (from-to)715-727
Number of pages13
JournalJournal of Neural Transmission
Volume127
Issue number5
DOIs
Publication statusPublished - May 2020

Keywords

  • Spinal cord injury (SCI)
  • Amyotrophic lateral sclerosis (ALS)
  • Human stromal
  • stem cells
  • Neuro-cells
  • Microglial activation
  • Methylprednisolone
  • Celecoxib
  • IL-1 beta
  • IL-6
  • GSK-3ss
  • IBA-1
  • AMYOTROPHIC-LATERAL-SCLEROSIS
  • MESENCHYMAL STEM-CELLS
  • SPINAL-CORD-INJURY
  • EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
  • FUNCTIONAL RECOVERY
  • ANIMAL-MODEL
  • CROSS-TALK
  • TRANSPLANTATION
  • EXPRESSION
  • DISEASE

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