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.
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 also 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. Our latest research with decorin shows that in addition to suppressing CSPGs, infusion of decorin into injured central nervous system can also suppress Semaphorin 3A another potent scar associated inhibitor of axon growth (4).
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.
Making the right astrocytes from glial precursors for CNS Repair
Stem cell based cell replacement therapies for the CNS have received a great deal of recent attention, however most researchers have concentrated on the replacement of damaged neurons and oligodendrocytes (axon ensheathing cells). Relatively little attention has been given to the replacement of astrocytes, despite the fact that they account for the vast majority (~70%) of total cells in the adult human brain and spinal cord. Recent studies have shown that astrocytes actually control: 1: axon (nerve fiber) sprouting, 2: the growth of dendrites (the cell processes on neurons that receive signals from axons), 3: development of new connections between neurons (called synapses) and 4: the transmission of signals between neurons at synapses. In light of these new insights into astrocyte biology it is readily apparent that astrocyte replacement should be a major goal of stem cell based therapies for the injured or diseased brain and spinal cord.
Working in collaboration with a research team at University of Rochester, NY (Drs. Christoph Proschel, Margot Mayer-Proschel and Mark Noble) our research team has developed a novel technology that allows us for the first time to make specific subtypes of astrocytes from embryonic multi-potent stem cells called glial restricted precursor cells (GRP cells). We have named one specific type of highly beneficial stem cell derived astrocyte - GRP derived astrocytes BMP or GDAsBMP, so called because they are derived from GRP cells treated with bone morphogenetic protein. Adult spinal cord injured rats treated with GDAsBMP showed ~40% in just 8 days and had returned to pre- injury scores in tests of coordinated limb movement by 2 to 4 weeks after treatment (5). In addition the GDAsBMP cells were also able to provide robust protection of injured neurons in the brain and spinal cord, a result that has important implications for treating stroke, ALS, Parkinson’s and Alzheimers disease.
Notably our studies highlight the importance of controlling the fate of stem cells to achieve optimal tissue repair as “naïve” GRP stem cells or another subtype of astrocyte generated by treating GRP cells with ciliary neurotrophic factor -GDAsCNTF - not only failed to promote functional recovery when transplanted into injured spinal cords but also cause pain syndromes, a severe side effect that was not seen in rats treated with GDAsBMP(6) In our latest study published in PLoS ONE we have generated the human form of the GDAsBMP cells and shown that transplantation of these specific human astrocytes can also promote robust functional recovery, axon growth and protection of spinal cord neurons in spinal cord injured rats (7). Our research team is now working to translate human GDAsBMP to use in treating human brain and spinal cord injuries.
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:
- 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
- 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
- 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
- Minor, K.H., Bournat, J.C., Toscano, N., Giger,R.J., Davies S.J.A. (2010) Decorin, erythroblastic leukaemia viral oncogene homologue B4 and signal transducer and activator of transcription 3 regulation of semaphorin 3A in central nervous system scar tissue Brain (online ) http://brain.oxfordjournals.org/content/early/2010/11/26/brain.awq304.long
- 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
- 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
- Davies S.J.A., Chung-Hsuan S., Noble M., Mayer-Proschel M. Proschel C and Davies J.E (2011) Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury. PLoS ONE (online) http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017328