The role of nervous system helper cells called astrocytes continues to unfold. These cells, once thought to be inert as a sort of spacer for neurons, are now known to play a crucial role in response to nervous system injury. It turns out there are many kinds of astrocytes; they can be good, or they can be bad. They can be neuroprotective and help form bridges for nerve fibers to grown on. But they can also form a tough barrier to growth, known as glial scar.
A recent research publication in the
Journal of Neuroscience from Lyn B. Jakeman of
Ohio State’s Center for Brain and Spinal Cord Repair reports that her team manipulated astrocytes that were on the bad side to become growth-supportive good ones.
Her paper is titled
Transforming Growth Factor alpha Transforms Astrocytes to a Growth-Supportive Phenotype after Spinal Cord Injury.
From the paper (citations omitted)
Astrocytes are both detrimental and beneficial for repair and recovery after spinal cord injury (SCI). These dynamic cells are primary contributors to the growth-inhibitory glial scar, yet they are also neuroprotective and can form growth-supportive bridges on which axons traverse….
During development, astrocyte precursors support growing axons and after SCI in lower vertebrates and very young mammals, astrocyte progenitors migrate from the ependymal zone to form a scaffold for regeneration. However, after SCI in adult mammals, astrocytes vacate the lesion core and form a cellular and molecular border at the lesion edge that is inhibitory to axon growth. Peripheral axons grow within the lesion, but few centrally derived axons are able to extend beyond the glial border. Even after removal of multiple inhibitory cues and profound stimulation of intrinsic growth potential, axonal growth is observed nearly exclusively in association with small remnants of astroglial bridges.
As the astrocyte gets more attention, there have been a number of attempts to transplant them or their precursors directly into the spinal cord. Results have been mixed. Says Jakeman:
… With increasing evidence of glial heterogeneity and plasticity, we propose that an attractive alternative strategy is to target the endogenous astrocyte response and stimulate the formation of growth-permissive cellular bridges to support growing axons.
In other words, she thinks astrocytes can be directed toward being helpful, but that they can’t do it on their own:
We have shown that intrathecal administration of transforming growth factor alpha (TGF alpha) to the contused mouse spinal cord can enhance astrocyte infiltration and axonal growth within the injury site, but the mechanisms of these effects are not well understood. The present studies demonstrate that the epidermal growth factor receptor (EGFR) is upregulated primarily by astrocytes and glial progenitors early after SCI. TGF alpha directly activates the EGFR on these cells in vitro, inducing their proliferation, migration, and transformation to a phenotype that supports robust neurite outgrowth.
Taking this a step further, Jakeman
et al wanted to see more closely what role EGFR played after spinal trauma. They used a special mutant mouse with dysfunctional EGFR. After injury, these mice had larger lesions, malformed glia borders and less recovery. The group also used a viral delivery gene transfer to instill the injured area with TGF alpha (thus spiking EGFR). This made axons grow better. So yes, it seems EGFR is useful and probably necessary for mounting repair after SCI. This leads Jakeman to the key point of the research: modifying astrocytes proliferation after injury, with a controlled stimulation of EGFR, might be a good strategy to enhance repair after SCI.
There’s a lot left to do. First, the use of TGF alpha to upregulate EGFR led only to a modest amount of repair. The techniques and methods, and the basic biology, have yet to be fully elucidated. Second, direct application of TGF alpha to the spinal cord is not itself a likely therapy; there is reasonably high risk of tumor formation. Still, the micro-biology of the injury site has been remodeled in this experiment toward more robust repair in the injured spinal cord. This, says the author, is the “first step toward tissue repair after SCI.”
