NG2-Expressing Neural Lineage Cells Derived from Embryonic Stem Cells Penetrate Glial Scar and Promote Axonal Outgrowth After Spinal Cord Injury


After a spinal cord injury, resident stem cells in the spinal cord contribute to the production of a glial scar that is rich in chondroitin sulfate proteoglycan (CSPG). The glial scar is a formidable barrier to axonal regeneration in the injured spinal cord, since CSPG actively repels growing axonal growth cones. Even though the glial scar seals off the spinal cord from further damage from inflammation, the long-term effects of the glial scar are to prevent regeneration of spinal nerves, which have the ability to regenerate in culture.

The major components of the site of injury include myelin debris, the scar-forming astrocytes, activated resident microglia and infiltrating blood-borne immune cells, chondroitin sulfate proteoglycans (CSPGs) and other growth-inhibitory matrix components. All of them are potential targets for therapeutic intervention. Many of the interventions can be optimized by considering the beneficial aspects of the scar tissue and fine-tuning the optimal time window for their application. Each target and the strategies directed at its modulation are shown.
The major components of the site of injury include myelin debris, the scar-forming astrocytes, activated resident microglia and infiltrating blood-borne immune cells, chondroitin sulfate proteoglycans (CSPGs) and other growth-inhibitory matrix components. All of them are potential targets for therapeutic intervention. Many of the interventions can be optimized by considering the beneficial aspects of the scar tissue and fine-tuning the optimal time window for their application. Each target and the strategies directed at its modulation are shown.

New work by Sudhakar Vadivelu, in the laboratory of John McDonald at the International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland has discovered new ways to breach the glial scar. Vadivelu and colleagues used a cell culture system that tested the ability of particular cells to help growing axonal growth cones penetrate glial scar material. This culture system showed that embryonic stem cell-derived neural lineage cells (ESNLCs) with prominent expression of nerve glial antigen 2 (NG2) survived, and passed through an increasingly inhibitory gradient of CSPG. These cells also expressed matrix metalloproteinase 9 (MMP-9) at the appropriate stage of their development, which helped poke holes in the CSPG. The outgrowth of axons from ESNLCs followed the NG2-expressing cells because the migrating cells chiseled pathways through the CSPG for the outgrowth of new axons.

To confirm these results in a living animal, Vadivelu and others transplanted embryonic stem cell-derived ESNLCs directly into the cavities of a contused spinal cord of laboratory animals 9 days after injury. One week later, implanted ESNLCs survived and expressed NG2 and MMP-9. The axons of these neurons had grown through long distances (>10 mm), although they preferred to grow across white rather than gray matter.

These data are consistent with CSPG within the injury scar acting as an important impediment to neuronal regeneration, but that NG2+ progenitors derived from ESNLCs can alter the microenvironment within the injured spinal cord to allow axons to grow through such a barrier. This beneficial action seems to be due, in part, at least, to the developmentally-regulated expression of MMP-9. Vadivelu and others conclude from these data that it might be possible to induce axonal regeneration in the human spinal cord by transplanting ESNLCs or other cells that express NG2.

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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