Transplantation of subventricular zone neural precursors induces an endogenous precursor cell response in a rat model of Parkinson's disease.
Realistically, future stem cell therapies for neurological conditions including Parkinson's disease (PD) will most probably entail combination treatment strategies, involving both the stimulation of endogenous cells and transplantation. Therefore, this study investigates these two modes of neural precursor cell (NPC) therapy in concert in order to determine their interrelationships in a rat PD model. Human placental alkaline phosphatase (hPAP)-labeled NPCs were transplanted unilaterally into host rats which were subsequently infused ipsilaterally with 6-hydroxydopamine (6-OHDA). The reaction of host NPCs to the transplantation and 6-OHDA was tracked by bromodeoxyuridine (BrdU) labeling. Two weeks after transplantation, in animals transplanted with NPCs we found evidence of elevated host subventricular zone NPC proliferation, neurogenesis, and migration to the graft site. In these animals, we also observed a significant preservation of striatal tyrosine hydroxylase (TH) expression and substantia nigra TH cell number. We have seen no evidence that neuroprotection is a product of dopamine neuron replacement by NPC-derived cells. Rather, the NPCs expressed glial cell line-derived neurotrophic factor (GDNF), sonic hedgehog (Shh), and stromal cell-derived factor 1 alpha (SDF1alpha), providing a molecular basis for the observed neuroprotection and endogenous NPC response to transplantation. In summary, our data suggests plausible synergy between exogenous and endogenous NPC actions, and that NPC implantation before the 6-OHDA insult can create a host microenvironment conducive to stimulation of endogenous NPCs and protection of mature nigral neurons.
Madhavan
Lalitha
L
Department of Neurology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
Daley
Brian F
BF
Paumier
Katrina L
KL
Collier
Timothy J
TJ
D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000601:surgery*; D016380:Brain Tissue Transplantation / Q000379:methods*; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D009498:Neurotoxins; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000503:physiopathology / Q000601:surgery*; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
D015415:Biomarkers; D054377:Chemokine CXCL12; D051100:Glial Cell Line-Derived Neurotrophic Factor; D053823:Hedgehog Proteins; D009498:Neurotoxins; D016627:Oxidopamine