Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha.
BACKGROUND
Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1alpha (SDF-1alpha) is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1alpha were explored. 6-hydroxydopamine (6-OHDA, 20 microg) was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 x 107 cells, respectively) or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1alpha were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA) assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining.


RESULTS
Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH)-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc) compared to that of control rats. In the in vitro study, SDF-1alpha treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups.


CONCLUSIONS
Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1alpha. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.
Wang
Feifei
F
Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Yasuhara
Takao
T
Shingo
Tetsuro
T
Kameda
Masahiro
M
Tajiri
Naoki
N
Yuan
Wen Ji
WJ
Kondo
Akihiko
A
Kadota
Tomohito
T
Baba
Tanefumi
T
Tayra
Judith Thomas
JT
Kikuchi
Yoichiro
Y
Miyoshi
Yasuyuki
Y
Date
Isao
I
D000661:Amphetamine; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D019610:Cytoprotection / Q000502:physiology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis; D005260:Female; D006085:Graft Survival / Q000502:physiology; D007262:Infusions, Intravenous; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015415:Biomarkers; D054377:Chemokine CXCL12; D009498:Neurotoxins; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine