This proposal is focused on application of recent advances in stem cell biology to a potential therapy for spinal cord injury. The proposed experiments will utilize mesenchymal stem cells derived from human bone marrow (marrow stromal cells, hMSCs), examine their phenotype following transplantation into spinal cord and test their ability to promote regeneration and recovery of function. Human MSCs are easy to obtain from a patient under local anesthesia, provide a renewal population and can be used for autologous grafting. Our preliminary data show that hMSCs grafted into spinal cord lesions survive, integrate well and appear to be permissive for axonal growth, and thus are excellent candidates for use in spinal core repair strategies. The full potential of hMSCs to differentiate is not well understood, but there is growing evidence that adult cells from bone marrow have remarkable plasticity and can assume diverse phenotypes dependent on the environment that they encounter. We reasoned that by transplanting hMSCs cells into spinal cord we can combine a systematic and direct examination of their fate in vivo with a detailed analysis of their therapeutic effects in neuronal rescue, axon regeneration and functional recovery in a well characterized model of spinal cord injury. Previous studies and our preliminary data suggest that hMSCs produce a variety of cytokines and neurotrophic factors that support survival and regeneration. The proposed experiments will examine the behavior of untreated and treated hMSCs in normal spinal cord (AIM 1) and in a well-characterized injury model of a unilateral C4 lesioned spinal cord (AIM 2). These cells will be analyzed with respect to their survival, migration and phenotype as well as their ability to rescue axotomized neurons (in the Red Nucleus), promote axon regeneration (of corticospinal and rubrospinal tracts) and restore function (using cylinder, rope and grid walking, reaching and patch removal tests). The therapeutic potential of different batches of hMSCs will then be correlated to their expression profile of secretory factors.
In Aim 3 we will study the ability of grafted hMSCs to deliver therapeutic genes (BDNF and NT3) to the injured spinal cord and the effects of the genetic modification on the phenotypic properties of these cells and the potential for repair and restoration of function. Taken together, these experiments will provide a through preclinical analysis of the properties and therapeutic potential of hMSCs in the injured CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043882-02
Application #
6529970
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S4))
Program Officer
Chiu, Arlene Y
Project Start
2001-09-30
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$215,175
Indirect Cost
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Himes, B Timothy; Neuhuber, Birgit; Coleman, Carl et al. (2006) Recovery of function following grafting of human bone marrow-derived stromal cells into the injured spinal cord. Neurorehabil Neural Repair 20:278-96
Swanger, Sharon A; Neuhuber, Birgit; Himes, B Timothy et al. (2005) Analysis of allogeneic and syngeneic bone marrow stromal cell graft survival in the spinal cord. Cell Transplant 14:775-86
Neuhuber, Birgit; Gallo, Gianluca; Howard, Linda et al. (2004) Reevaluation of in vitro differentiation protocols for bone marrow stromal cells: disruption of actin cytoskeleton induces rapid morphological changes and mimics neuronal phenotype. J Neurosci Res 77:192-204
Bakshi, Ajay; Hunter, Corey; Swanger, Sharon et al. (2004) Minimally invasive delivery of stem cells for spinal cord injury: advantages of the lumbar puncture technique. J Neurosurg Spine 1:330-7