Stephen Davies, Ph.D.
Associate Professor
Department of Neurosurgery,
University of Colorado Denver
http://www.youtube.com/watch?v=48U5T0uKV2w

Molecular and cell biology of repairing the traumatically injured adult mammalian central nervous system.

When axons are severed by traumatic injury to the adult mammalian central nervous system (CNS), the surviving portion of an axon still connected to the neuron cell body often sprouts but ultimately fails to regenerate across the site of injury. This failure of axons to regenerate and re-connect with former target circuits results in a loss of nervous system function. Traumatic CNS injuries also result in the loss of glia support cells that are vitally important for maintaining the structure and function of the nervous system. The brain and spinal cord often reacts to inflammation and the loss of glia at sites of injury by rapidly forming a fibrous meshwork of dense scar tissue directly in front of the cut ends of axons that are attempting to regenerate. Glial scar tissue is rich in molecules such as chondroitin sulfate proteoglycans (CSPGs), semaphorins and ephrins that are known to be inhibitory to axon growth and thus CNS scar tissue presents a combined physical and molecular barrier to axon regeneration.

My research program at UC Denver is focused on developing two, complementary approaches to repairing the injured central nervous system (CNS): 1) overcoming the effects of axon growth inhibitors found at sites of injury and throughout the environment of the injured adult CNS and 2), development of glial restricted precursor derived astrocyte (GDA) technologies to generate specific types of astrocyte glia that are suitable for repairing the injured or diseased spinal cord and brain.

1.) Overcoming axon growth inhibitors
My research team has shown that a naturally occurring antagonist of scar formation, a small leucine rich proteoglycan called decorin, is highly effective at suppressing inflammation, synthesis of CSPGs and fibrous scar formation when infused into acute spinal cord injuries in rats (1).  More importantly decorin infusion permitted the rapid growth of axons across sites of injury in just 4 days (1) . CSPGs and myelin associated inhibitory molecules are also thought to play prominent roles in regulating plasticity of connections in the normal and injured CNS. My lab has recently demonstrated that decorin has the remarkable ability to directly desensitize adult neurons to the axon growth inhibitory effects of multiple CSPGs and myelin associated inhibitors (2) and induce the injured spinal cord to synthesize Plasmin (3) , an enzyme that has the ability to degrade multiple CSPGs. In light of these findings my lab is investigating the ability of decorin to induce neural circuit plasticity in the acute and chronically injured adult CNS.

 2.) GRP derived astrocytes and CNS repair
Stem cell / precursor transplantation based therapies for repairing the injured or diseased CNS have recently received a great deal of both scientific and public attention. However, most researchers have concentrated on the replacement of damaged neurons and oligodendrocytes with relatively little attention given to the potential importance of astrocyte replacement therapies, despite the fact that astrocytes account for the majority of total cells in the adult CNS and are critical for normal CNS function. We have recently shown that a specific sub-type of astrocyte derived from BMP treatment of stem cell-like embryonic glial restricted precursor cells (GRPs) can promote a high efficiency of axon regeneration and functional recovery after transplantation to adult rat spinal cord injuries (4) . In addition we have found that glial restricted precursor derived astrocytes (GDAs) induced by BMP (GDAs BMP) are also highly neuro-protective for injured neurons in the brain such as red nucleus neurons (4) . This protective effect of GDAs BMP has major implications for using these cells for treatment of other traumatic CNS injuries e.g. traumatic brain injury and Stroke as well as neurodegenerative diseases such as Cerebral Palsy, Alzheimer’s, Parkinson’s, Multiple Sclerosis and Amyotrophic Lateral Sclerosis (ALS).

Making Gains without Pain
At present very little is known about the function of different types of astrocytes in the mammalian CNS. An important question arising from our initial GDA studies was whether the two types of astrocytes that can be generated from embryonic spinal GRP cells (called GDAs BMP and GDAs CNTF because of their derivation from GRPs treated with BMP or gp130 receptor agonists such as CNTF) would differ in their ability to promote CNS repair.  We have found that GDAs CNTF or indeed “naïve” undifferentiated GRP cells do not provide any of the benefits associated with GDAs BMP when transplanted into spinal cord injuries i.e. no axon regeneration or functional recovery (5) . Nor are these cells neuro-protective for injured red nucleus (5) . Importantly, we found that transplantation of GDA CNTF cells and also of “naïve” GRP cells into acute spinal cord caused both mechanical allodynia and thermal hyperalgesia forms of neuropathic pain (5) . Notably, pre-differentiation of GRP cells to GDAs BMP did not promote pain syndromes further demonstrating the potential value of this specific population of astrocytes in treatment of the injured CNS (5) . Our GDA studies demonstrate for the first time that not all astrocytes that can be derived from embryonic stem or precursor cells are equal and that controlled pre-differentiation of stem cell / precursors to a specific type of astrocyte prior to transplantation is required to promote CNS repair and avoid severe side effects such as neuropathic pain.

Through gaining a greater understanding of the underlying molecular and cellular biology that governs both failure and success of the adult CNS to regenerate, our ultimate goal is to provide clinically relevant strategies to promote efficient tissue repair and functional recovery of the injured or diseased human central nervous system. 

Recent relevant publications:

1. Davies, J. E., Tang, X., Denning, J. W., Archibald, S. J., Davies, S. J. (2004) Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries. Eur.J Neurosci. 19, 1226-1242

2. Minor, K., Tang, X., Kahrilas, G., Archibald, S. J., Davies, J. E., Davies, S. J. (2008) Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons. Neurobiol.Dis. 32, 88-95

3. Davies, J. E., Tang, X., Bournat, J. C., Davies, S. J. (2006) Decorin Promotes Plasminogen/Plasmin Expression within Acute Spinal Cord Injuries and by Adult Microglia In Vitro. J Neurotrauma 23, 397-408

4. Davies, J. E., Huang, C., Proschel, C., Noble, M., Mayer-Proschel, M., Davies, S. J. (2006) Astrocytes derived from glial-restricted precursors promote spinal cord repair. J Biol. 5, 7 http://jbiol.com/content/5/3/7

5. Davies, J. E., Proschel, C., Zhang, N., Noble, M., Mayer-Proschel, M., Davies, S. J. (2008) Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury. J Biol. 7, 24 http://jbiol.com/content/7/7/24

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