Xiao-Ming Xu, Ph.D.
Scientific Director, Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute
Professor and Mari Hulman George Chair of Neurological Surgery
Professor of Anatomy and Cell Biology
Professor of Pharmacology and Toxicology
Ph.D., The Ohio State University (1990)
Neuroprotection and Functional Regeneration following Spinal Cord Injury.
The goal of our laboratory is to study mechanisms underlying spinal cord injury (SCI) and develop novel repair strategies to improve anatomical reorganization and functional recovery in experimental models of SCI. Our long-term goal is to translate effective treatments from animal models to humans. To reach these goals, two lines of research are being conducted. First, we aim at acute neuroprotection by investigating novel targets that may play central roles in mediating progressive secondary degeneration in the spinal cord after injury. Our recent work suggests that phospholipase A2 (PLA2), a diverse family of phospholipid enzymes, may be such a molecule. We are currently studying mechanisms underlying PLA2-mediated spinal cord secondary injury including mitochondria dysfunction, and PLA2-RhoA/Rho Kinase interaction and signaling pathways. We are also testing agents that may block PLA2-RhoA/Rho Kinase-mediated cytotoxicity and cell death to enhance neuroprotection and recovery of function in animal models of SCI. A second line of research is to use cellular transplantation strategies to promote axonal regeneration through and beyond a lesion gap after SCI. SCI incurs disconnection of nerve fibers (called axons) and a successful repair strategy requires reconnection of these axons to their appropriate targets. Grafts of tissue engineered scaffolds seeded with different growth-supportive cells, such as Schwann cells (SCs), oligodendrocyte progenitor cells (OPCs), or immature astrocytes derived from embryonic stem cells, may provide a necessary cellular alignment and environment to guide and support axonal regeneration through the lesion gap and beyond. We combined cell-based therapy with other efficacious treatments including boosting the intrinsic regenerative capacity of injured CNS neurons, overcoming the inhibitory environment associated with the glial scar and CNS myelin, providing growth-promoting pathways along the course of axonal regeneration, and enhancing synaptic reconnection between regenerating axons and their targets. Ultimately, the final repair of the injured spinal cord may be achievable by combining an early phase of neuroprotection, a delayed phase of transplantation-mediated axonal regeneration, and vigorous rehabilitation strategies. Researches along these lines are being conducted. The following are highlights of major ongoing research projects conducted in our laboratory:
- Cell transplantation-based regeneration for spinal cord repair. These cells include Schwann cells, oligodendrocyte progenitor cells (OPCs), and embryonic stem cell-derived immature astrocytes.
- Intrinsic and extrinsic mechanisms of corticospinal tract (CST) axonal regeneration
- Inflammation, glucocorticoid receptors, and cell death mechanisms
- Role of phospholipase A2 in mediating spinal cord secondary injury
- Characterization of repetitive mild traumatic brain injury (mTBI)
Selected Recent Publications (from 25 peer-reviewed publications, 2013-2015):
- Wu WJ, Wu W, Zou J, Shi F, Yang S, Liu Y, Lu P, Ma Z, Zhu H, Xu X-M (2013) Axonal and glial responses to a mid-thoracic spinal cord hemisection in the Macaca fascicularis monkey. J Neurotrauma 30:826-839 [PMID:23421822]
- Deng L, Deng P, Ruan Y, Xu ZC, Liu N, Wen X, Smith GM, Xu X-M (2013) A novel growth-promoting pathway formed by GDNF-overexpressing Schwann cells promotes propriospinal axonal regeneration, synapse formation, and partial recovery of function after spinal cord injury. J Neurosci 33:5655-5667 [PMID: 23536080]
- Wang X, Hu J, She Y, Smith GM, Xu X-M (2013) Cortical PKC inhibition promotes axonal regeneration of the corticospinal tract and forelimb recovery after cervical dorsal spinal hemisection in adult rats Cerebral Cortex 24:3069-3079, 2014 [PMID: 23810979]
- Hu J, Wang X, Deng L, Liu N, Gao X, Chen JH, Zhou F, Xu X-M (2013) Co-transplantation of glial restricted precursor cells and Schwann cells promotes functional recovery after spinal cord injury Cell Transplant 22:2219-2236. DOI: 10.3727/096368912X661373 (with Cover Image)
- Wu W, Lee S-Y, Xu X, Tyler J, Wang H, Ouyang Z, Park K, Xu X-M*, Cheng J-X* (2013) Neuroprotective ferulic acid (FA) – glycol chitosan (GC) nanoparticles for functional restoration of traumatically injured spinal cord. Biomaterials 35:2355-2364
- Liu N-K, Deng L-X, Zhang YP, Lu Q-B, Wang X-F, Hu J-G, Oakes E, Shields CB, Xu, X-M (2014) cPLA2 protein as a novel therapeutic target for spinal cord injury Ann Neurol 75(5):644-58.
- Wang, XF, Xu X-M (2014) Long-term survival, axonal growth-promotion, and myelination of Schwann cells grafted into contused spinal cord in adult rats. Exp Neurol 261:308-319. [doi:10.1016/j.expneurol.2014.05.022]
- Liu N-K, Zhang Y-P, Zou J, Verhovshek T, Chen C, Lu Q-B, Walker CL, Shields BS, Xu X-M (2014) A semicircular controlled cortical impact produces long-term motor and cognitive dysfunction that correlates well with damage to both the sensorimotor cortex and hippocampus. Brain Res 1576:18-26, 2014.
- Walker CL, Wang XF, Bullis C, Liu N-K, Lu Q, Fry C, Deng L, Xu X-M (2015) Biphasic bisperoxovanadium administration and Schwann cell transplantation for repair after cervical contusive spinal cord injury. Exp Neurol 264:163-172.
- Wang H, Liu N-K, Zhang YP, Deng LX, Lu QB, Shields CB, Walker MJ, Li J, Xu X-M (2015) Treadmill training induced lumbar motoneuron dendritic plasticity and behavior recovery in adult rats after a thoracic contusive spinal cord injury. Exp. Neurol. (In press)
- Wang H, Zhang YP, Cain J, Tuchek CA, Shields LBE, Shi R, Li J, Shields CB, Xu X-M (2015) A Compact blast brain injury device produces graded injury severities, neuronal degeneration and functional deficits. J Neuropath Exp Neurol, (In press)
- Deng L, Ruan Y, Chen C, Frye CC, Xiong W, Jin X, Jones K, Sengelaub, Xu X-M (2015) Characterization of dendritic morphology and neurotransmitter phenotype of thoracic descending propriospinal neurons after complete spinal cord transection and GDNF treatment. Exp Neurol (In press) (NIHMS 749250)
Other significant publications (from 154 peer-reviewed publications)
- Xu XM, Martin GF (1989) Developmental plasticity of the rubrospinal tract in the North American opossum. J Comp Neurol 279:368-381.
- Xu XM, Martin GF (1991) Evidence for new growth and regeneration of cut axons in developmental plasticity of the rubrospinal tract in the North American opossum. J Comp Neurol 313:103-112.
- Xu XM, Guénard V, Kleitman N, and Bunge MB (1995a) Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J Comp Neurol 351:145-160.
- Xu XM, Guénard V, Kleitman N, Bunge MB (1995b) A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol 134:261-272.
- Xu XM, Chen A, Guénard V, Kleitman N, Bunge MB (1997) Bridging Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord. J Neurocytol 26:1-16.
- Liu XZ, Xu XM, Hu R, Cheng D, Zhang SX, McDonald JW, Dong HX, Wu YJ, Fan GS, Jacquin MF, Hsu CY, Choi DW (1997) Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 17:5395-5406.
- Yan P, Xu J, Li Q, Chen SW, Kim G-M, Hsu CY, Xu XM (1999) Gluococorticoid receptor expression in the spinal cord after traumatic injury in adult rats. J Neurosci 19: 9355-9363.
- Xu XM, Zhang S-X, Li H, Aebischer P, Bunge MB (1999) Regrowth of axons into the distal spinal cord through a Schwann cell-seeded mini-channel implanted into hemisected adult rat spinal cord. Eur J Neurosci 11:1723-1740.
- Kim GM, Xu J, Xu J, Song S-K, Yan P, Ku G, Xu XM, Hsu CY (2001) Tumor necrosis factor receptor deletion reduces nuclear factor-kB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. J Neurosci 21:6617-6625.
- Warden P, Bamber NI, Li H, Esposito A, Ahmad KA, Hsu CY, Xu XM (2001) Delayed glial cell death following Wallerian degeneration in white matter tracts after spinal cord dorsal column cordotomy in adult rats. Exp. Neurol. 168:213-224.
- Bamber NI, Li H, Lu X, Oudega M, Aebischer P, and Xu XM (2001) Neurotrophins BDNF and NT-3 promote axonal re-entry into the distal host spinal cord through Schwann cell-seeded mini-channels. Eur J Neurosci 13:257-268.
- Xu J, G-M Kim, Ahmed SH, Xu J, Yan P, Xu XM, Hsu CY (2001) Glucocorticoid receptor-mediated suppression of AP-1 activation and matrix metalloproteinase expression after spinal cord injury. J Neurosci 21:92-97.
- Kim E-S, Kim G-M, Lu X, Hsu CY, Xu XM (2002) Neural connection in the adult rat CNS after spinal cord injury – A study using fast blue and the bartha strain of Pseudorabies virus. J. Neurotrauma 19:787-800.
- Chau, C.H., Shum, D.K.Y., Li, H., Pei, J., Lui, Y.Y., Wirthlin, L., Chan, Y.S. and Xu, X.M. (2004) Chondroitinase treatment enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury. FASEB J. 18: 194-196.
- Sivasankaran, R., Pei, J., Wang, K.C., Zhang, Y.P., Shields, C.B., Xu, X.-M.* and He, Z.* (2004) Protein kinase C mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration. Nat. Neurosci. 7:261-268.
- Cao Q, Xu X-M, DeVries WH, Enzmann GU, Ping PP, Tsoulfas P, Wood PM, Bunge MB, and Whittemore SR (2005) Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J Neurosci 25:6947-6957. [PMID: 2813488]
- Liu NK, Zhang YP, Titsworth WL, Jiang X, Han S, Lu PH, Shields CB and Xu X-M (2006) A Novel Role of Phospholipase A2 in Mediating Spinal Cord Secondary Injury. Annal Neurol 59:606-619.
- Liu Y, Wang X, Sherman R, Lu C-C, Steward O*, Xu X-M*, Zou Y* (2008) Repulsive Wnt signaling inhibits axon regeneration following central nervous system injury. J Neurosci 28:8376-8382
- Zhang L, Ma Z, Smith GM, Wen X, Pressman Y, Wood PM, Xu X-M (2009) GDNF-enhanced axonal regeneration and myelination following spinal cord injury is mediated by primary effects on neurons. Glia 57:1178-1191 (DOI: 10.1002/glia.20840)
- Titsworth WL, Cheng X, Ke Y, Deng L, Burckardt KA, Pendleton C, Liu N-K, Shao H, Cao Q-L, Xu X-M (2009) Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death. Glia 1521-1537. [PMID: 19306380]
- Shi F, Zhu H, Yang S, Liu Y, Feng Y, Shi J, Xu D, Wu W, You S, Ma Z, Zou J, Lu P, Xu X-M (2009) Glial response and myelin clearance in areas of Wallerian degeneration after spinal cord hemisection in the monkey Macaca Fascilularis. J Neurotrauma 26:2083-2096. [PMID: 19456214]
- Liu N-K, Wang X, Lu Q-B, Xu X-M (2009) Altered MicroRNA Expression following Traumatic Spinal Cord Injury. Exp Neurol 219:424-429. [NIHMSID-133042; PMID-19576215; PMCID-2810508].
- Cao Q, He Q, Wang Y, Cheng X, Howard RM, Zhang Y, DeVries WH, Shields CB, Magnuson DSK, Xu X-M, Kim DH, Whittemore SR (2010) Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinal cord injury. J Neurosci. 30:2989-3001.