Protection of nigral neurons by GDNF-engineered marrow cell transplantation

• Published in: Neuroscience research 2001-08, Vol.40 (4), p.315-323
• Main Authors: Park, Kun-Woo, Eglitis, Martin A., Mouradian, M.Maral
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - physiology; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Bone Marrow Transplantation - methods; Cells, Cultured - cytology; Cells, Cultured - metabolism; Cells, Cultured - transplantation; DNA, Complementary - genetics; Dopamine - biosynthesis; Female; GDNF; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Motor Activity - genetics; MPTP; Nerve Growth Factors; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - metabolism; Parkinson; Parkinsonian Disorders - genetics; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - therapy; Recovery of Function - genetics; Substantia Nigra - drug effects; Substantia Nigra - pathology; Substantia Nigra - surgery; Transfection - methods; Transplantation; Tyrosine 3-Monooxygenase - biosynthesis; Tyrosine hydroxylase
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/S0168-0102(01)00242-5

Marrow stromal cells, which have many characteristics of stem cells, populate various non-hematopoietic tissues including the brain. In the present study, the cDNA for the dopaminergic neurotrophic factor Glial Cell Line-Derived Neurotrophic Factor (GDNF) was delivered using marrow cells in the mouse 1-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) model of Parkinson's disease. Following cross-sex intravenous bone marrow transplantation with male donor cells that had been transduced with GDNF (GDNF-BMT) or with non-manipulated marrow (Control-BMT), female recipient mice were subjected to systemic MPTP injections. Eight weeks after neurotoxin exposure, more tyrosine hydroxylase immunoreactive nigral neurons and striatal terminal density were observed in the GDNF-BMT mice compared with the Control-BMT group. In addition, following the expected initial behavioral hyperactivity in both groups, a significant difference in motor activity was detected between the two groups. GDNF immunoreactive male donor marrow derived cells were detected in the brains of GDNF-BMT mice but not in controls. These data indicate that marrow derived cells that seed the brain can express biologically active gene products and, therefore, can function as effective vehicles for therapeutic gene transfer to the brain.