Xiao-Ming Xu, PhD
Mari Hulman George Professor of Neuroscience Research
The goal of our laboratory is to study mechanisms underlying spinal cord injury (SCI) and traumatic brain injury (TBI) and to develop novel repair strategies to promote neural reorganization and functional recovery in experimental models of these injuries. Our long-term goal is to translate promising treatments from animal models to humans, including our veterans.
To reach these goals, two lines of research are being conducted. The first line of research is on neuroprotection. Our lab was among the first to report apoptosis following acute SCI, and to report phospholipase A2 as a key mediator of secondary SCI. The second line of research is on axonal regeneration. We were among the first to transplant Schwann cells (SCs) into injured spinal cords to promote axonal regeneration and recovery of function. In addition to SCs, we also transplant other glial cells including oligodendrocyte progenitor cells (OPCs) and human embryonic stem cell (hESC)-derived immature astrocytes in their ability to support neural circuitry reorganization and recovery of function. These cell-based strategies are combined with other efficacious treatments on boosting intrinsic and extrinsic regenerative capacities. We are particularly interested in promoting regeneration and/or reorganization of long descending supraspinal axons such as those from the corticospinal tract (CST), the rubrospinal (RST) and the descending propriospinal tract (dPST).
In our research, we apply cutting-edge and multidisciplinary approaches including novel injury models, cellular and molecular biology, in vivo imaging, optogenetics, electrophysiology, behavioral, and histology/immunohistochemistry approaches.
If you would like to learn more, please visit our lab website here.
About Dr. Xu:
Dr. Xiao-Ming Xu received his Medical Diploma (1975) from Shanghai Second Medical University (now Shanghai Jiaoting University School of Medicine), Master of Medicine from Shanghai Medical University (MM, now Fudan University School of Medicine), and Ph.D. in Anatomy/Neurobiology from The Ohio State University (OSU, Columbus, OH). He is currently a Professor and Mari Hulman George Chair of Neurological Surgery, and the Scientific Director of the Indiana University Spinal Cord and Brain Injury Research Group (ISCBIRG) at the Stark Neurosciences Research Institute (SNRI), Indiana University School of Medicine (IUSM). Dr. Xu is also a VA Research Scientist (GS-15) at Roudebush VA Medical Center (VAMC) in Indianapolis, IN Dr. Xu’s research has focused on neuroprotection, and cell transplantation-mediated axonal regeneration and recovery of function following spinal cord injury (SCI). He has received continuous support from the National Institutes of Health (NIH) for over 20 years. He has also received support from the Department of Defense (DOD), Department of Veterans Affairs (VA) and Craig H Neilsen Foundation. He has served as a standing member on NIH study sections CNNT (2006-2010) and NSD-A (2012-2018). He has published over 170 research papers in prestige scientific journals such as Nature Neuroscience, Journal of Neuroscience, Annals of Neurology, Cerebral Cortex, Glia, and Journal of Neurotrauma. He has edited 3 books entitled “Animal Models of Acute Neurological Injuries (Vol. 1 & Vol. 2)” and “Neural Regeneration”. He is the Editor-in-Chief of the journal Neural Regeneration Research. He is on the Editorial Boards of Journal of Neurotrauma, Experimental Neurology, and Cell Transplantation. He is the Organizing Committee Co-Chair of the International Neural Regeneration Symposiums (2011-2018).
Chen C, Zhang YP, Sun Y, Xiong W, Shields L, Shields CB, Jin X, and Xu X-M* (2017) An in vivo Duo-color Method for imaging Vascular Dynamics Following Contusive Spinal Cord Injury. J. Vis. Exp. (accepted)
Lin XJ, Zhao T, Xiong W, Wen S, Jin X, Xu X-M* (2017) Imaging neural activity in the primary somatosensory cortex using Thy1-GCaMP6s transgenic mice. J. Vis. Exp. (accepted)
Al-Ali H, Ding Y, Slepak T, Wu W, Sun Y, Martinez Y, Xu X-M*, Lemmon V*, Bixby J* (2017) The mTOR substrate S6 Kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for Central Nervous System. J. Neurosci. 37:7079-7095. DOI: https://doi.org/10.1523/JNEUROSCI.0931-17.2017
Wu W, Xiong W, Zhang YP, Chen L, Fang J, Shields CB,Xu X-M*, Jin X* (2017) Increased threshold of short-latency motor evoked potentials in transgenic mice expressing Channelrhodopsin-2. Plus ONE (accepted).
Lee HJ, Zhang D, Jiang Y, Wu XB, Shih P-Y, Liao C-S, Bungart B, Xu X-M, Drenan R, Bartlett E, Cheng J-X (2017) Label-free vibrational spectroscopic imaging of neuronal membrane potential. J. Physical Chem. Ltr. 8:1932-1936
Wu XB, Zhang YP, Qu W, Shields LBE, Shields CB, and Xu X-M* (2017) A Tissue Displacement Based Contusive Spinal Cord Injury Model in Mice. J. Vis. Exp. (124) e54988, doi:10.3791/54988.
Indiana University Health Neuroscience Research Bldg. 320 W. 15th Street, Suite 500E
Indianapolis, IN 46202
Titles & Appointments
- Professor of Neurological Surgery
- Adjunct Professor of Anatomy & Cell Biology
- Adjunct Professor of Pharmacology & Toxicology
The following are brief descriptions of the ongoing research projects conducted in our laboratory (*: corresponding author):
1. Glucocorticoid receptor, inflammation, and cell death: In collaboration with Chung Hsu at Washington University, St. Louis, we were among the first to identify apoptotic cell death following SCI. We systemically investigated inflammation cascades including the expression of TNFα, TNF receptors, and transcription factors NF-κB and AP-1. We investigated the expression and functional role of the glucocorticoids receptor (GR) in mediating the structural and functional outcomes after SCI. Both pharmacological and genetic approaches were used in these studies.
1. 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.
2. 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.
3. 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.
4. 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.
2. Phospholipase A2 as a novel target for neuroprotection: Phospholipase A2 (PLA2) is a diverse family of lipolytic enzymes. We found that the total PLA2 activity and expression, as well as the expression of cytosolic PLA2 (cPLA2) and secretory PLA2-IIA (sPLA2-IIA), increased following SCI. Exogenous administration of PLA2 induced inflammatory, oxidation, motor dysfunction, and demyelination. Inhibition of PLA2 with annexin A1 (ANX-A1), a PLA2 inhibitor, in a rat SCI model showed inhibition of inflammation and neuroprotection. Currently, we are investigating whether PLA2 serves as a common pathway that mediates multiple injury mechanisms and whether blocking PLA2 can be an attractive strategy to improve tissue repair and functional recovery.
1. Liu N-K, 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.
2. 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]
3. Liu NK, Byers JS, Lam T, Lu Q, Sengelaub DR, Xu X-M* (2014) Inhibition of cPLA2 has neuroprotective effects on motoneuron and muscle atrophy following spinal cord injury J Neurotrauma Nov 11. [Epub ahead of print].
4. 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
3. Schwann cell transplantation: Working with Drs. Richard and Mary Bartlett Bunge, I was among the first to transplant Schwann cells (SCs) into the injured spinal cord to promote axonal regeneration following spinal cord injury (SCI). This earlier work, along with others, provided the scientific rationale for the clinical trial of autologous SC transplantation in human SCI patients being conducted at the Miami Project to Cure Paralysis, University of Miami. Currently, my laboratory has been testing combinatorial strategies involving SC transplantation, delivery of trophic factors, and removal of glial scar to enhance the survival, regeneration, and recovery of function in animal models of SCI and to translate these strategies to pre-clinical settings.
1. 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.
2. 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.
3. 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.
4. 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.
4. Corticospinal regeneration: The corticospinal tract (CST) is one of the main motor pathways of the spinal cord and is particularly important for hand function. A major effort in my laboratory is to promote corticospinal regeneration/plasticity after various treatments. Two major strategies were tested: 1) inhibition of conventional protein kinases C (PKC) at the lesion site and motor cortex (In collaboration with Dr. Zhigang He at Harvard Medical School), and 2) inhibition of Wnt signaling (In collaboration with Dr. Yimin Zou at UCSD). Both strategies yielded promising results. We are now studying whether regeneration/plasticity of CST axons could form a new functional relay within the injured spinal cord to promote recovery of motor function.
1. 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.
2. 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.
3. 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. Advance Access Publication June 28, 2013; Printed Publication 24:3069-3079, 2014 [PMID: 23810979]
4. Al-Ali H, Ding Y, Slepak T, Wu W, Sun Y, Martinez Y, Xu X-M, Lemmon V*, Bixby J* (2017) The mTOR substrate S6 Kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for Central Nervous System. J. Neurosci. 37:7079-7095. DOI: https://doi.org/10.1523/JNEUROSCI.0931-17.2017
5. Traumatic brain injury: As a Scientific Director of the Spinal Cord and Brain Injury Research Group (SCBIRG), I also contribute to the TBI Consortium Group at IUSM by establishing several well-accepted models of TBI and by developing new TBI models for our own need. Using these models, we are currently studying 1) the role of cPLA2 in the TBI model, and 2) whether blocking PSD-95 and nNOS interaction results in neuroprotection (with Dr. Anantha Shekhar at IUSM) .
1. Liu NK, Zhang Y-P, O’Connor J, Gianaris A, Oakes E, Lu Q-B, Verhovshek T, Walker C, Shields CB, Xu X-M* (2013) A bilateral head injury that shows graded brain damage and behavior deficits in adult mice Brain Research 1499:121-128 [PMID:23276498]
2. 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.
3. Wang H, Zhang YP, Cain J, Tuchek CA, Shields LBE, Shi R, Li J, Shields CB, Xu X-M* (2016) A Compact blast brain injury device produces graded injury severities, neuronal degeneration and functional deficits. J Neuropath Exp Neurol 271:368-378, 2016.