Recent studies show that bone marrow-derived stem cells differentiate into microglia, astrocytes, and neurons. A variety of preparations, including crude bone marrow, marrow stromal cells, and hematopoietic stem cells have been used for transplantation into animal models. Brain injury may enhance this differentiation. We plan to compare the potential of different bone marrow preparations to differentiate into brain cells in a mouse model of neonatal hypoxic-ischemic (HI) injury. Our hypothesis is that undifferentiated bone marrow assists in recovery from this injury by the contribution of cells which differentiate into cerebral endothelial cells, astrocytes, oligodendrocytes, and neurons.
Our specific aims are: 1) determine the expression of neural and endothelial markers in cells arising from exogenous bone marrow preparations in injured brain of the bone marrow recipient, and 2) determine if bone marrow-derived cells develop into functioning neurons and glial cells after HI injury. In this proposal we will deliver the HI injury to female mice on the seventh postnatal day. At eight weeks of age, they will undergo irradiation and receive bone marrow transplants from male mice of the same strain, some transgenic for Green Fluorescent Protein (GFP). The cells for transplantation will be prepared as crude marrow, marrow stromal cells or hematopoietic stem cells. The animals will be sacrificed at intervals after the transplant for immunohistochemical assessment of the male (Y chromosome) and GFP cells resulting in brain, followed by electrophysiologic testing of the GFP cells. This proposal satisfies the aims of the R21 model. We plan to obtain preliminary data for a future proposal which will deal with methods of enhancing bone marrow-derived cells in brain. Also, the proposal undertakes the novel use of a neonatal injury model, with the animals treated at a later age. This approach mimics what would occur in a clinical situation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS043439-02
Application #
6623256
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Chiu, Arlene Y
Project Start
2002-06-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$140,630
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Neurology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Hill, William D; Hess, David C; Martin-Studdard, Angeline et al. (2004) SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol 63:84-96
Irons, H; Lind, J G; Wakade, C G et al. (2004) Intracerebral xenotransplantation of GFP mouse bone marrow stromal cells in intact and stroke rat brain: graft survival and immunologic response. Cell Transplant 13:283-94
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