Hans S. KeirsteadAssistant Professor, Anatomy & Neurobiology |
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Research Interests |
Regeneration, degeneration, spinal cord, injury, myelin, demyelination, axon, growth cone, and plasticity | |
| URL | www.ucihs.uci.edu/anatomy/keirstead.html | |
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Research Abstract |
1. Preventing the phase of secondary degeneration that follows an initial trauma 2. Removing growth-inhibitory myelin from the vicinity of an injury site, facilitating axonal regeneration 3. Transplanting human stem cell derivatives into regions of spinal cord injury The focus of the Keirstead laboratory is the development of strategies to limit degeneration and enhance regeneration after spinal cord injury, of both axons and myelin. Currently, the laboratory has three primary research areas, 1) preventing the phase of secondary degeneration that follows an initial trauma; secondary degeneration normally occurs after a traumatic injury, increasing the size of the lesion and the resulting functional deficit, 2) removing growth-inhibitory myelin from the vicinity of an injury site, which allows axons to regenerate, and 3) transplanting growth-permissive cell populations into regions of spinal cord injury in order to repair lost myelin and provide an environment that favors axon regeneration. These therapies are often combined in an effort to further enhance repair. For treatment of acute SCI, the Keirstead laboratory is investigating strategies to reduce or eliminate the posttraumatic enlargement of spinal cord injury sites that normally occurs after traumatic injury. This process is largely mediated by the immune system, and the laboratory has developed methods of inhibiting the deleterious components of the immune response to CNS injury. These methods of reducing the immune response to injury result in a near elimination of secondary degeneration, which means that far less tissue is lost after an injury and functional impairment is greatly decreased. The human reagents necessary for clinical trials have recently been generated, and the program is being developed for human therapy. The removal of myelin from the spinal cord is another method developed to treat spinal cord injury. Myelin inhibits regrowth of injured fibers, so the removal of myelin around an injury site renders the spinal cord permissive for repair. Our lab has demonstrated that this treatment is effective in facilitating repair of spinal cord injuries in chickens, rats and mice. Stem Cell Research Dr. Keirstead was the first researcher in North America to gain access to the federally approved hESC lines for CNS trauma research. He is Co-Director of the UCI Stem Cell Research Initiative, has testified to the CA Senate on several occasions regarding the potential of stem cells, was an advisor to the Davis CA government on stem cell policy, represented the spinal cord research community at an NIH-sponsored policy meeting in Sweden to advise the NIH on stem cell funding issues, is a Scientific Advisory Board Member of the California Stem Cell Initiative, and maintains working relationships with several stem cell companies and venture capital groups in the United States and Sweden. His stem cell research forms the basis of a clinical trial that is being developed (i.e. it is in the pre-clinical phase). His current stem cell research utilizes 2 hESC lines. He developed a method to differentiate hESC lines into high purity oligodendrocyte progenitor populations, demonstrating for the first time that hESC lines can be differentiated into high purity CNS populations, and making available for the first time high purity human oligodendroglial lineage cells for research and therapy. He subsequently transplanted these cells into acute and chronic spinal cord injured adult rats, and demonstrated that the cells survived, differentiated into myelinating oligodendrocytes, and restored locomotor ability in paralyzed animals. In this manner he is comparing the regenerative efficacy of different hESC lines, as well as young and old passage hESC lines. He is also investigating the ability of transplanted hESC derivatives to migrate in the adult CNS following manipulation of the environment. Finally, he is conducting gene chip and other molecular analyses of hESCs and their derivatives to determine points of control during their differentiation, and the effects on hESC derivatives following exposure to the injured CNS. |
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| Publications | Gabriel I. Nistor, Minodora O. Totoiu, Nadia Haque, Melissa K. Carpenter and Hans S. Keirstead (2004) Differentiation of oligodendrocytes in high-purity from human embryonic stem cells. Glia (in press). | |
| Janette Glaser, Rafael Gonzalez, Victoria Perreau, Carl W. Cotman and Hans S. Keirstead (2004) Neutralization of the chemokine CXCL10 enhances tissue sparing and angiogenesis following spinal cord injury. J. Neurosci. Res. 77: 701-708. | ||
| Roya Azanchi, Giovanna Bernal, Ranjan Gupta and Hans S. Keirstead (2004) Combined demyelination plus Schwann cell transplantation therapy increases spread of cells and axonal regeneration following contusion injury. J. Neurotrauma 21:775-88. | ||
| Minodora O. Totoiu, Gabriel I. Nistor, Thomas E. Lane and Hans S. Keirstead (2004) Remyelination and Locomotor Recovery Following Transplantation in the MHV Model of Multiple Sclerosis. Exp. Neurol. 187: 254-265. (cover) | ||
| Rafael Gonzalez, Janette Glaser, Michael T. Liu, Thomas E. Lane and Hans S. Keirstead (2003) Reducing the T lymphocyte response to spinal cord injury decreases posttraumatic degeneration and functional impairment. Exp. Neurol. 184: 456-463. | ||
| Binhai Zheng, Hans Keirstead, Oswald Steward, Marc Tessier-Lavigne (2003) Lack of Extensive Spinal Regeneration in Nogo-deficient mice Neuron 38:1-20. | ||
| Liu, M.T., Keirstead, H.S. and Lane, T.E. (2001) Neutralization of the CXC chemokine IP-10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis. J. Immunol. 167:4091-7. | ||
| G.L. Hinks, D.M. Chari, M.T. O’Leary, C. Zhao, H.S. Keirstead, W.F. Blakemore and R.J.M. Franklin (2001) Depletion of endogenous oligodendrocyte progenitors rather than increased availability of survival factors is a likely explanation for enhanced survival of transplanted oligodendrocyte progenitors in X-irradiated compared to normal CNS. Neuropathology & Applied Neurobiology 27:59-67. | ||
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Keirstead, H.S., Morgan, S., Wilby, M.J. and Fawcett, J.W. Enhanced axonal regeneration following demyelination plus Schwann cell transplantation therapy in the injured adult spinal cord. Exp. Neurol., 1999, 159: 225-236. |
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Blakemore, W.F. and Keirstead, H.S. The origin of remyelinating cells in the adult CNS. Journal of Neuroimmunology, 1999, 98: 69-76. |
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| Keirstead, H.S., Ben-Hur, T., Rogister, B., O'Leary, M., Dubois-Dalcq, M. and Blakemore, W.F. PSA-NCAM+ CNS precursors generate both oligodendrocytes and Schwann cells to remyelinate the CNS following transplantation. Journal of Neuroscience, 1999, 19: 7529-7536. | ||
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Keirstead, H.S., Hughes, H.G. and Blakemore, W.F. A quantifiable model of axonal regeneration in the demyelinated adult spinal cord. Experimental Neurology, 1998, 151: 303-313. |
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Keirstead, H.S., Levine, J.M. and Blakemore, W.F. Response of the oligodendrocyte progenitor cell population (as defined by NG2 labelling) to demyelination in the adult CNS. Glia, 1998, 22: 161-170. |
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Keirstead, H.S. and Blakemore, W.F. Identification of post-mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord. J. Neuropathol. Exp. Neurol., 1997, 56: 1191-1201. |
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Keirstead, H.S., Pataky, D.M., McGraw, J. and Steeves, J.D. In vivo immunological suppression of spinal cord myelin development. Brain Research Bulletin, 1997, 44: 727-734. |
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Keirstead, H.S., Dyer, J.K., Sholomenko, G.N., McGraw, J., Delaney, K.R. and Steeves, J.D. (1998) Axonal regeneration and physiological activity following transection and immunological disruption of myelin within the hatchling chick spinal cord. Journal of Neuroscience, 1995, 15: 6963-6974. |
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Hasan, S.J., Keirstead, H.S., Muir, G.D., Steeves, J.D. (1998) Regeneration contributes to repair of transected spinal cord in embryonic chick. Journal of Neuroscience, 1993, 13(2): 492-507. |
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Keirstead, H.S., Hasan, S.J., Muir, G.D., Steeves, J.D. Suppression of the onset of myelination extends the permissive period for the functional repair of embryonic spinal cord. Proceedings of the National Academy of Science, USA1992, 89: 11664-11668. |
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Professional Society |
Society for Neuroscience,
Downing College, Cambridge |
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| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=4554 | |
| Last updated | 10/14/2004 | |