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Could NG2 Provide a Break Through for Spinal Cord Injury?

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Review of “NG2+ Progenitors Derived From Embryonic Stem Cells Penetrate Glial Scar and Promote Axonal Outgrowth into White Matter after Spinal Cord Injury” from Stem Cells TM by Stuart P. Atkinson.

Glial scarring represents an important barrier to axonal regeneration following spinal cord injuries, and any means to bypass, or “break through”, this barrier may aid in the treatment of this debilitating injury. The glial scar forms to protect and begin the healing process in the nervous system and is composed of chondroitin sulfate proteoglycan (CSPG). Research published recently in Stem Cells TM by Sudhakar Vadivelu (University of Cincinnati College of Medicine) now shows that transplantation of embryonic stem cell-derived neural lineage cells (ESNLCs) expressing nerve glial antigen 2 (NG2) represents an exciting new strategy to encourage axonal regeneration in the human spinal cord mediated by a breakdown of the glial scar [1].

The researchers began by differentiating ESCs towards the neural lineage using a previously published and well used protocol [2], and found that 43% of cells in the embryoid bodies (EBs) which formed expressed NG2 and so represented tripotential neural progenitors [3-5]. After plating EBs on dense aggrecan (a CSPG) monolayers the predominating GFAP-negative/NG2-positive cell population presented with a halo surrounding them, suggesting cellular migration by degradation of CSPGs. Furthermore, NG2-expressing ESNLCs were able to digest and pass through a rim of high aggrecan concentration and low laminin concentration in a functional inhibitory model of the glial scar in vitro [6]. The adjoining figure depicts green neurites unable to pass through the red CSPG gradient (A), an ESNLC (black arrow) migrating through the CSPG spot gradient (B), the black gap through the CSPG zone made by the ESNLCs (C), and finally neural processes passing through the CSPG gap (D). The matrix metalloproteinase 9 (MMP-9) mediated the cellular penetration of the rim, and this promoted the co-passage of -tubulin-positive processes of other ESNLCs. The researchers then studied their findings in vivo through the transplant of ESNLCs into contusion injury cavity which, at 9 days after injury, displayed a prominent glial scar. Encouragingly, the researchers observed robust axonal outgrowth through the scar and into white matter mediated by NG2-positive and MMP-9 positive penetrative cells.

Overall, this report provides support that an ESC-derived cell population may act to regenerate the human spinal cord after glial scarring has occurred, and in so doing, may give hope to those sufferers of SCI. This novel finding, mediated by NG2 and MMP-9 could be further enhanced through modification of ESCs to express higher levels of each protein, leading to greater destruction of the glial scar and therefore promotion of axonal regeneration.

References

  1. Vadivelu S, Stewart TJ, Qu Y, et al. NG2+ Progenitors Derived From Embryonic Stem Cells Penetrate Glial Scar and Promote Axonal Outgrowth Into White Matter After Spinal Cord Injury. Stem Cells Translational Medicine 2015;4:401-411.
  2. Bain G, Kitchens D, Yao M, et al. Embryonic stem cells express neuronal properties in vitro. Developmental biology 1995;168:342-357.
  3. Liu S, Qu Y, Stewart TJ, et al. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proceedings of the National Academy of Sciences of the United States of America 2000;97:6126-6131.
  4. McDonald JW, Liu XZ, Qu Y, et al. Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nature medicine 1999;5:1410-1412.
  5. Qu Y, Vadivelu S, Choi L, et al. Neurons derived from embryonic stem (ES) cells resemble normal neurons in their vulnerability to excitotoxic death. Experimental neurology 2003;184:326-336.
  6. Tom VJ, Doller CM, Malouf AT, et al. Astrocyte-associated fibronectin is critical for axonal regeneration in adult white matter. The Journal of neuroscience : the official journal of the Society for Neuroscience 2004;24:9282-9290.