Following traumatic spinal cord injury (SCI), three major cellular deficits need to be addressed to attempt therapeutic repair: regeneration of severed axons, myelination of demyelinated and regeneration axons, and replacement of lost neurons. Both the fetal and adult CNS contain pluripotent stem cells that can be expanded in vitro and will differentiate into astrocytes oligodendrocytes and/or neurons. We hypothesize that transplantation of CNS stem cells, whose phenotyping fate can be precisely controlled in vitro, into the injured spinal cord may foster endogenous axonal regeneration and remyelination and enable functional neuronal replacement and circuit restoration.
Aim 1 will establish cellular and molecular approaches that direct cell-specific differentiation of stem cells into astrocytes, neurons, and oligodendrocytes.
Aim 2 will determine the lineage restriction of CNS stem cells in the lesioned spinal cord. The lesioned CNS has distinctive white and gray matter environments rostral to, caudal to, or at the injury epicenter and the epigenetic signals in these diverse cellular terrains will direct very different neural precursor cell differentiation. We hypothesize that the constitutive differentiated phenotypes in vivo will be different from those in vitro, and variables for cell-specific differentiation in vivo will have to be empirically determined in vitro before grafting.
Aim 3 will determine the physiological potential of CNS stem cells to engender repair in SCI. Stem cells with defined phenotypes in vivo will be used to address three specific deficits in adult rat SCI: a) remyelinate axons after transplantation into the demyelinated spinal cord, and b) integrate into host circuitry and receive afferent input after transplantation into the contused spinal cord. We hypothesize that judicious choice of differentiated cell typed and neurotrophic factor delivery for particular lesions will enable improved anatomical and potentially behavioral recovery subsequent to stem cell transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
1P01NS038665-01A2
Application #
6333135
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
$53,568
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Williams, Ryan R; Henao, Martha; Pearse, Damien D et al. (2015) Permissive Schwann cell graft/spinal cord interfaces for axon regeneration. Cell Transplant 24:115-31
Flora, Govinder; Joseph, Gravil; Patel, Samik et al. (2013) Combining neurotrophin-transduced schwann cells and rolipram to promote functional recovery from subacute spinal cord injury. Cell Transplant 22:2203-17
Williams, Ryan R; Pearse, Damien D; Tresco, Patrick A et al. (2012) The assessment of adeno-associated vectors as potential intrinsic treatments for brainstem axon regeneration. J Gene Med 14:20-34
Hill, Caitlin E; Brodak, Danika M; Bartlett Bunge, Mary (2012) Dissociated predegenerated peripheral nerve transplants for spinal cord injury repair: a comprehensive assessment of their effects on regeneration and functional recovery compared to Schwann cell transplants. J Neurotrauma 29:2226-43
Maggio, Dominic M; Chatzipanteli, Katina; Masters, Neil et al. (2012) Acute molecular perturbation of inducible nitric oxide synthase with an antisense approach enhances neuronal preservation and functional recovery after contusive spinal cord injury. J Neurotrauma 29:2244-9
Hill, Caitlin E; Guller, Yelena; Raffa, Scott J et al. (2010) A calpain inhibitor enhances the survival of Schwann cells in vitro and after transplantation into the injured spinal cord. J Neurotrauma 27:1685-95
Fortun, Jenny; Hill, Caitlin E; Bunge, Mary Bartlett (2009) Combinatorial strategies with Schwann cell transplantation to improve repair of the injured spinal cord. Neurosci Lett 456:124-32
Talbott, Jason F; Cao, Qilin; Bertram, James et al. (2007) CNTF promotes the survival and differentiation of adult spinal cord-derived oligodendrocyte precursor cells in vitro but fails to promote remyelination in vivo. Exp Neurol 204:485-9
Golden, Kevin L; Pearse, Damien D; Blits, Bas et al. (2007) Transduced Schwann cells promote axon growth and myelination after spinal cord injury. Exp Neurol 207:203-17
Davis, Angela R; Lotocki, George; Marcillo, Alex E et al. (2007) FasL, Fas, and death-inducing signaling complex (DISC) proteins are recruited to membrane rafts after spinal cord injury. J Neurotrauma 24:823-34

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