Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease

Takao Yasuhara, Noriyuki Matsukawa, Koichi Hara, Guolong Yu, Lin Xu, Mina Maki, Seung U. Kim, Cesario V. Borlongan

Research output: Contribution to journalArticle

199 Citations (Scopus)

Abstract

Neural stem cells (NSCs) possess high potencies of self-renewal and neuronal differentiation. We explored here whether transplantation of human NSCs cloned by v-myc gene transfer, HB1.F3 cells, is a feasible therapeutic option for Parkinson's disease. In vivo, green fluorescent protein-labeled HB1.F3 cells (200,000 viable cells in 3 μl of PBS) when stereotaxically transplanted (same-day lesion-transplant paradigm) into the 6-hydroxydopamine-lesioned striatum of rats significantly ameliorated parkinsonian behavioral symptoms compared with controls (vehicle, single bolus, or continuous minipump infusion of trophic factor, or killed cell grafts). Such graft-derived functional effects were accompanied by preservation of tyrosine hydroxylase (TH) immunoreactivity along the nigrostriatal pathway. Grafted HB1.F3 cells survived in the lesioned brain with some labeled with neuronal marker mitogen-activated protein 2 and decorated with synaptophysin-positive terminals. Furthermore, endogenous neurogenesis was activated in the subventricular zone of transplanted rats. To further explore the neuroprotective mechanisms underlying HB1.F3 cell transplantation, we performed cell culture studies and found that a modest number of HB1.F3 cells were TH and dopamine and cAMP-regulated phosphoprotein 32 positive, although most cells were nestin positive, suggesting a mixed population of mature and immature cells. Administration of the HB1.F3 supernatant to human derived dopaminergic SH-SY5Y cells and fetal rat ventral mesencephalic dopaminergic neurons protected against 6-hydroxydopamine neurotoxicity by suppressing apoptosis through Bcl-2 upregulation, which was blocked by anti-stem cell factor antibody alone, the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4- one] alone, or a combination of both. These results suggest that HB1.F3 cell transplantation exerts neuroprotective effects against dopaminergic depletion in vitro and in vivo because of trophic factor secretion and neuronal differentiation.

Original languageEnglish
Pages (from-to)12497-12511
Number of pages15
JournalJournal of Neuroscience
Volume26
Issue number48
DOIs
Publication statusPublished - Nov 29 2006
Externally publishedYes

Fingerprint

Neural Stem Cells
Parkinson Disease
Transplantation
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Oxidopamine
Cell Transplantation
Tyrosine 3-Monooxygenase
Transplants
Dopamine and cAMP-Regulated Phosphoprotein 32
Phosphatidylinositol 3-Kinase
Neuroprotection
Nestin
Behavioral Symptoms
Synaptophysin
myc Genes
Stem Cell Factor
Lateral Ventricles
Dopaminergic Neurons
Neurogenesis
Neuroprotective Agents

Keywords

  • Apoptosis
  • Neurodegeneration
  • Neurogenesis
  • Neuroprotection
  • Stem cell factor
  • Trophic

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease. / Yasuhara, Takao; Matsukawa, Noriyuki; Hara, Koichi; Yu, Guolong; Xu, Lin; Maki, Mina; Kim, Seung U.; Borlongan, Cesario V.

In: Journal of Neuroscience, Vol. 26, No. 48, 29.11.2006, p. 12497-12511.

Research output: Contribution to journalArticle

Yasuhara, Takao ; Matsukawa, Noriyuki ; Hara, Koichi ; Yu, Guolong ; Xu, Lin ; Maki, Mina ; Kim, Seung U. ; Borlongan, Cesario V. / Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 48. pp. 12497-12511.
@article{30c57dc3dd75404282797ef732a77997,
title = "Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease",
abstract = "Neural stem cells (NSCs) possess high potencies of self-renewal and neuronal differentiation. We explored here whether transplantation of human NSCs cloned by v-myc gene transfer, HB1.F3 cells, is a feasible therapeutic option for Parkinson's disease. In vivo, green fluorescent protein-labeled HB1.F3 cells (200,000 viable cells in 3 μl of PBS) when stereotaxically transplanted (same-day lesion-transplant paradigm) into the 6-hydroxydopamine-lesioned striatum of rats significantly ameliorated parkinsonian behavioral symptoms compared with controls (vehicle, single bolus, or continuous minipump infusion of trophic factor, or killed cell grafts). Such graft-derived functional effects were accompanied by preservation of tyrosine hydroxylase (TH) immunoreactivity along the nigrostriatal pathway. Grafted HB1.F3 cells survived in the lesioned brain with some labeled with neuronal marker mitogen-activated protein 2 and decorated with synaptophysin-positive terminals. Furthermore, endogenous neurogenesis was activated in the subventricular zone of transplanted rats. To further explore the neuroprotective mechanisms underlying HB1.F3 cell transplantation, we performed cell culture studies and found that a modest number of HB1.F3 cells were TH and dopamine and cAMP-regulated phosphoprotein 32 positive, although most cells were nestin positive, suggesting a mixed population of mature and immature cells. Administration of the HB1.F3 supernatant to human derived dopaminergic SH-SY5Y cells and fetal rat ventral mesencephalic dopaminergic neurons protected against 6-hydroxydopamine neurotoxicity by suppressing apoptosis through Bcl-2 upregulation, which was blocked by anti-stem cell factor antibody alone, the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4- one] alone, or a combination of both. These results suggest that HB1.F3 cell transplantation exerts neuroprotective effects against dopaminergic depletion in vitro and in vivo because of trophic factor secretion and neuronal differentiation.",
keywords = "Apoptosis, Neurodegeneration, Neurogenesis, Neuroprotection, Stem cell factor, Trophic",
author = "Takao Yasuhara and Noriyuki Matsukawa and Koichi Hara and Guolong Yu and Lin Xu and Mina Maki and Kim, {Seung U.} and Borlongan, {Cesario V.}",
year = "2006",
month = "11",
day = "29",
doi = "10.1523/JNEUROSCI.3719-06.2006",
language = "English",
volume = "26",
pages = "12497--12511",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "48",

}

TY - JOUR

T1 - Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease

AU - Yasuhara, Takao

AU - Matsukawa, Noriyuki

AU - Hara, Koichi

AU - Yu, Guolong

AU - Xu, Lin

AU - Maki, Mina

AU - Kim, Seung U.

AU - Borlongan, Cesario V.

PY - 2006/11/29

Y1 - 2006/11/29

N2 - Neural stem cells (NSCs) possess high potencies of self-renewal and neuronal differentiation. We explored here whether transplantation of human NSCs cloned by v-myc gene transfer, HB1.F3 cells, is a feasible therapeutic option for Parkinson's disease. In vivo, green fluorescent protein-labeled HB1.F3 cells (200,000 viable cells in 3 μl of PBS) when stereotaxically transplanted (same-day lesion-transplant paradigm) into the 6-hydroxydopamine-lesioned striatum of rats significantly ameliorated parkinsonian behavioral symptoms compared with controls (vehicle, single bolus, or continuous minipump infusion of trophic factor, or killed cell grafts). Such graft-derived functional effects were accompanied by preservation of tyrosine hydroxylase (TH) immunoreactivity along the nigrostriatal pathway. Grafted HB1.F3 cells survived in the lesioned brain with some labeled with neuronal marker mitogen-activated protein 2 and decorated with synaptophysin-positive terminals. Furthermore, endogenous neurogenesis was activated in the subventricular zone of transplanted rats. To further explore the neuroprotective mechanisms underlying HB1.F3 cell transplantation, we performed cell culture studies and found that a modest number of HB1.F3 cells were TH and dopamine and cAMP-regulated phosphoprotein 32 positive, although most cells were nestin positive, suggesting a mixed population of mature and immature cells. Administration of the HB1.F3 supernatant to human derived dopaminergic SH-SY5Y cells and fetal rat ventral mesencephalic dopaminergic neurons protected against 6-hydroxydopamine neurotoxicity by suppressing apoptosis through Bcl-2 upregulation, which was blocked by anti-stem cell factor antibody alone, the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4- one] alone, or a combination of both. These results suggest that HB1.F3 cell transplantation exerts neuroprotective effects against dopaminergic depletion in vitro and in vivo because of trophic factor secretion and neuronal differentiation.

AB - Neural stem cells (NSCs) possess high potencies of self-renewal and neuronal differentiation. We explored here whether transplantation of human NSCs cloned by v-myc gene transfer, HB1.F3 cells, is a feasible therapeutic option for Parkinson's disease. In vivo, green fluorescent protein-labeled HB1.F3 cells (200,000 viable cells in 3 μl of PBS) when stereotaxically transplanted (same-day lesion-transplant paradigm) into the 6-hydroxydopamine-lesioned striatum of rats significantly ameliorated parkinsonian behavioral symptoms compared with controls (vehicle, single bolus, or continuous minipump infusion of trophic factor, or killed cell grafts). Such graft-derived functional effects were accompanied by preservation of tyrosine hydroxylase (TH) immunoreactivity along the nigrostriatal pathway. Grafted HB1.F3 cells survived in the lesioned brain with some labeled with neuronal marker mitogen-activated protein 2 and decorated with synaptophysin-positive terminals. Furthermore, endogenous neurogenesis was activated in the subventricular zone of transplanted rats. To further explore the neuroprotective mechanisms underlying HB1.F3 cell transplantation, we performed cell culture studies and found that a modest number of HB1.F3 cells were TH and dopamine and cAMP-regulated phosphoprotein 32 positive, although most cells were nestin positive, suggesting a mixed population of mature and immature cells. Administration of the HB1.F3 supernatant to human derived dopaminergic SH-SY5Y cells and fetal rat ventral mesencephalic dopaminergic neurons protected against 6-hydroxydopamine neurotoxicity by suppressing apoptosis through Bcl-2 upregulation, which was blocked by anti-stem cell factor antibody alone, the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4- one] alone, or a combination of both. These results suggest that HB1.F3 cell transplantation exerts neuroprotective effects against dopaminergic depletion in vitro and in vivo because of trophic factor secretion and neuronal differentiation.

KW - Apoptosis

KW - Neurodegeneration

KW - Neurogenesis

KW - Neuroprotection

KW - Stem cell factor

KW - Trophic

UR - http://www.scopus.com/inward/record.url?scp=33845258753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845258753&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3719-06.2006

DO - 10.1523/JNEUROSCI.3719-06.2006

M3 - Article

C2 - 17135412

AN - SCOPUS:33845258753

VL - 26

SP - 12497

EP - 12511

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 48

ER -