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Aortic occlusion will induce paralysis. Using a well-developed model of thoracic aortic occlusion with a 2 F Fogarty catheter passed from the femoral artery of the rat, we have shown that the mechanism of such ischemic deficit is primarily the result of a selective degeneration of small inhibitory GABA-ergic and glycinergic neurons localized in lumbosacral segments. Using a technique of selective spinal cord cooling we have also shown that a moderate intraischemic or early postischemic spinal hypothermia can provide a significant protection. However, once a significant population of spinal neurons is lost the corresponding neurological deficit is irreversible. Recently, using isolated spinal neuronal precursors or human hNT cells we have shown a long-term survival and rapid maturation of grafted cells at 2-3 months after transplantation if implanted into previously ischemic spinal cord segments. Majority of grafted cells developed inhibitory neurotransmitter phenotype (GABA) as confirmed by confocal microscopy. Significant improvement of neurological function and improvement in motor evoked potentials was also seen. Further studies will employ several other cell lines including human neural precursors or pluripotent stem cell lines and analyzed for their therapeutic potential when grafted spinally in animals with ischemia-induced paraplegia. The goal will be to identify differentiation potential, long term survival and functionality of grafted cells. In addition, electronoptical analysis will be used to identify the development of synapses between grafted cells and persisting host neurons.
References (Selected From 117 Publications)
Emre N, Vidal JG, Elia J, O'Connor ED, Paramban RI, Hefferan MP, Navarro R, Goldberg DS, Varki NM, Marsala M, Carson CT.The ROCK Inhibitor Y-27632 Improves Recovery of Human Embryonic Stem Cells after Fluorescence-Activated Cell Sorting with Multiple Cell Surface Markers. PLoS One. 2010 Aug 13;5(8).
Usvald D, Vodicka P, Hlucilova J, Prochazka R, Motlik J, Strnadel J, Kucharova K, Johe K, Marsala S, Scadeng M, Kakinohana O, Navarro R, Santa M, Hefferan MP, Yaksh TL, Marsala M. Analysis of dosing regimen and reproducibility of intraspinal grafting of human spinal stem cells in immunosuppressed minipigs. Cell Transplant. 2010 Apr 21.
Lunn JS, Pacut C, Backus C, Hong Y, Johe K, Hefferan M, Feldman EL, Marsala M. The Pleotrophic Effects of IGF-I on Human Spinal Cord Neural Progenitor Cells. Stem Cells Dev. 2010 Apr 20.
Lunn JS, Hefferan MP, Marsala M, Feldman EL.Stem cells: comprehensive treatments for amyotrophic lateral sclerosis in conjunction with growth factor delivery.Growth Factors. 2009 Jun;27(3):133-40
Hefferan ML, Kucharova K, Kinjo K, Kakinohana O, Sekerkova G, Nakamura S, Fuchigami T, Tomori Z, Yaksh TL, Kurtz N, Marsala M. Spinal astrocyte glutamate receptor 1 overexpression after ischemic insult facilitates behavioral signs of spasticity and rigidity. J Neurosci. 27:11179-11191, 2007.
Hedlund E, Hefferan MP, Marsala M, Isacson O. Cell therapy and stem cells in animal models of motorneuron disorders. Eur J Neurosci. 26:1721-1737., 2007
Cizkova D, Kakinohana O, Kucharova K, Marsala S, Johe K, Hazel T, Hefferan MP, Marsala M. Functional recovery in rats with ischemic paraplegia after spinal grafting of human spinal stem cells. Neurosci. 147:546-560, 2007.
Kucharova K, Lukacova N, Pavel J, Radonak J, Hefferan MP, Kolesar D, Kolessaova M, Marsala M, Marsala J. Spatiotemporal alterations of the NO/NOS neuronal pools following transient abdominal aorta occlusion: morphological and biochemical studies in the rabbit Cell Mol Neurobiol. 26:1295-1310, 2006.
Marsala M, Kakinohana O, Yaksh TL, Tomori Z, Marsala S, Cizkova D. Spinal implantation of hNT neurons and neuronal precursors: graft survival and functional effects in rats with ischemic spastic paraplegia. Eur J Neurosci;20:2401-14, 2004
Kakinohana O, Cizkova D, Tomori Z, Hedlund E, Marsala S, Isacson O, Marsala M. Region-specific cell grafting into cervical and lumbar spinal cord in rat: a qualitative and quantitative stereological study. Exp Neurol. 190:122-32, 2004