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Spinal Cord Treatment Problems – Site not the Cells?

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Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

From Stem Cells

Neural stem or precursor cells (NSPCs) have tremendous promise for use in cell-based therapies for the treatment of spinal cord injury (SCI) as they have been shown to provide trophic support following transplantation, allowing modification of the host environment to allow some endogenous regeneration and repair in animal models (Aboody et alBarnabe-Heider and Frisen, and Martino and Pluchino).   However, few studies have assessed their role in the chronic phase of SCI (Tetzlaff et al) and any correlation to microenvironmental factors (Thuret et al), which is potentially important for the behaviour of transplanted NSPCs.   Now, in a study published in Stem Cells from the laboratory of Seiji Okada at Kyushu University, Japan, Kumamaru et al combine flow-cytometric isolation and RNA-Seq to analyse the transcriptome of NSPCs transplanted into SCI during the chronic phase, and have demonstrated that while the cells have a positive therapeutic effect, the refractory state of the chronically injured spinal cord hampers locomotory recovery.

To determine the chronic phase of SCI, a time course of the change in the number of inflammatory cells until 3 months after SCI was assessed.   Neutrophil infiltration peaked at 12 hours and subsequently decreased, microglia increased and peaked at 6 weeks, while macrophages and monocytes first peaked at 12 hours and then again at 6 weeks.   Gene expression analysis over the same time period found that levels of pro-inflammatory factors, anti-inflammatory factors, CXC chemokine ligands and CC chemokine ligands and growth and neurotrophic factors were very different between the acute (enriched in inflammatory cytokine/chemokines and neurotrophic factors) and the chronic (enriched in growth factors) stages of SCI.   Next, Luciferase and GFP-labeled NSPCs were transplanted 3 months after SCI, where long-term cell viability was observed and graft survival rate of around 17% was observed at 42 days after transplantation.   Transplanted NSPCs migrated up to 4mm rostrally or caudally from the graft site and had extended fine cellular processes.   Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of transplanted cell migration and survival and have been linked to transplant failure during the chronic phase (Karimi-Abdolrezaee et al).   Analysis found that while CSPGs were abundant during the sub-acute phase of SCI, this reduced to normal levels at three months.

Subsequent RNA-Seq analysis of NSPCs analysed at 7 days after transplantation during the acute, sub-acute, and chronic phases of SCI found, as observed previously (Kumamaru et al), that transcriptional activity is reduced in NSPCs transplanted into the acutely injured spinal cord compared to those transplanted into naïve spinal cords, however this reduction was not observed for the sub-acute and chronic phases, and increased transcriptional activity was observed in chronically transplanted NSPCs.   Principal component analysis then suggested that sub-acutely injured spinal cords may promote the oligodendrocyte differentiation of transplanted NSPCs whereas chronically injured spinal cords promoted neuronal differentiation.   Analysis of differentiation-associated gene expression found that chronically injured spinal cords were permissive for the differentiation of engrafted NSPCs with overexpressed genes representing neurogenesis and neuronal differentiation.   Oligodendrocyte generation by engrafted NSPCs was not however inhibited in chronic SCI microenvironments but was more prominent in sub-acute SCI.   Secreted molecules, which can act as trophic mediators, decreased markedly in acutely injured spinal cords but increased in chronically injured spinal cords.  Finally, functional improvement was analysed and, while NSPC transplantation in the acute and sub-acute groups showed significantly improved functional recovery, the chronically NSPC-transplanted mice did not exhibit improved locomotor recovery.  

Overall, this study shows that NSPCs which are transplanted into chronic phase SCI sites survive, are migratory, transcriptionally active, undergo neuronal and oligodendrocyte differentiation and secrete trophic factors at a level higher than expected from a refractory site, BUT, ultimately do not improve locomotor function.   This suggests that the micro-environment of SCI in the chronic phase itself is the main barrier to the potential regenerative effects of NSPC transplantation.   With this knowledge in hand, therapies for this type of injury will hopefully continue to evolve to a state where cell therapy and environmental modulation can work hand in hand to affect functional recovery.

 

References

  • Aboody K et al. Translating stem cell studies to the clinic for CNS repair: current state of the art and the need for a rosetta stone. Neuron 2011; 70: 597–613
  • Barnabe-Heider F, Frisen J. Stem cells for spinal cord repair. Cell Stem Cell 2008; 3: 16–24
  • Karimi-Abdolrezaee S et al. Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J Neurosci 2010; 30: 1657–1676
  • Kumamaru H et al. Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells. Nat Commun 2012; 3: 1140
  • Martino G, Pluchino S. The therapeutic potential of neural stem cells. Nat Rev Neurosci 2006; 7: 395–406
  • Tetzlaff W et al. A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma 2011; 28: 1611–1682
  • Thuret S et al. Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 2006; 7: 628–643

From Stem Cells.

Stem Cell Correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.