Long-Term Survival of Human Central Nervous System Progenitor Cells Transplanted into a Rat Model of Parkinson's Disease

doi:10.1006/exnr.1997.6634

Experimental Neurology

Volume 148, Issue 1, November 1997, Pages 135-146

https://doi.org/10.1006/exnr.1997.6634 Get rights and content

Abstract

Progenitor cells were isolated from the developing human central nervous system (CNS), induced to divide using a combination of epidermal growth factor and fibroblast growth factor-2, and then transplanted into the striatum of adult rats with unilateral dopaminergic lesions. Large grafts were found at 2 weeks survival which contained many undifferentiated cells, some of which were migrating into the host striatum. However, by 20 weeks survival, only a thin strip of cells remained at the graft core while a large number of migrating astrocytes labeled with a human-specific antibody could be seen throughout the striatum. Fully differentiated graft-derived neurons, also labeled with a human-specific antibody, were seen close to the transplant site in some animals. A number of these neurons expressed tyrosine hydroxylase and were sufficient to partially ameliorate lesion-induced behavioral deficits in two animals. These results show that expanded populations of human CNS progenitor cells maintained in a proliferative state in culture can migrate and differentiate into both neurons and astrocytes following intracerebral grafting. As such these cells may have potential for development as an alternative source of tissue for neural transplantation in degenerative diseases.

References (45)

P. Brundin et al.
Monitoring of cell viability in suspensions of embryonic CNS tissue and its use as a criterion for intracerebral graft survival
Brain Res.
(1985)
P. Brundin et al.
Neuronal transplantation in rat models of Parkinson's and Huntington's disease
Semin. Neurosci.
(1993)
M. Buc-Caron
Neuroepithelial progenitor cells explanted from human fetal brain proliferate and differentiatein vitro
Neurobiol. Dis.
(1995)
T. Friedmann
Gene therapy for neurological disorders
TIG
(1994)
C. Gensburger et al.
Brain basic fibroblast growth factor stimulates the proliferation of rat neuronal precursor cellsin vitro
FEBS Lett.
(1987)
J.P. Hammang et al.
Transplantation of epidermal growth factor-responsive neural stem cell progeny into the murine central nervous system
Methods Neurosci.
(1994)
O.V. Kopyov et al.
Clinical study of fetal mesencephalic intracerebral transplants for the treatment of Parkinson's disease
Cell Transplant.
(1996)
C. Lundberg et al.
Generation of DOPA-producing astrocytes by retroviral transduc-tion of the human tyrosine hydroxylase gene:In vitroin vivo
Exp. Neurol.
(1996)
C. Lundberg et al.
Conditionally immortalized neural progenitor cells grafted to the striatum exhibit site-specific neuronal differentiation and establish connections with the host globus pallidus
Neurobiol. Dis.
(1996)
S.L. Minger et al.
Long-term survival of transplanted basal forebrain cells following in vitro propagation with fibroblast growth factor-2
Exp. Neurol.
(1996)

T.D. Palmer et al.

The adult rat hippocampus contains primordial neural stem cells

Mol. Cell. Neurosci.

(1997)

M. Peschanski et al.

Rationale for intrastriatal grafting of striatal neuroblasts in patients with Huntington's disease

Neuroscience

(1995)

L.L. Pundt et al.

Transplantation of human fetal striatum into a rodent model of Huntington's disease ameliorates locomotor deficits

Neurosci. Res.

(1996)

L.L. Pundt et al.

The fate of human glial cells following transplantation in normal rodents and rodent models on neurodegenerative disease

Brain Res.

(1995)

B.A. Reynolds et al.

Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell

Dev. Biol.

(1996)

G.M. Smith et al.

Transplantation of immature and mature astrocytes and their effect on scar formation in the lesioned central nervous system

Prog. Brain Res.

(1988)

D.L. Stemple et al.

Neural stem cells are blasting off

Neuron

(1997)

C. Svendsen et al.

Restricted growth potential of rat striatal precursors as compared to mouse

Dev. Brain Res.

(1997)

C.N. Svendsen et al.

Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system

Exp. Neurol.

(1996)

C.N. Svendsen et al.

Neurons from stem cells?

TINS

(1995)

U. Ungerstedt et al.

Quantitative recording of rotational behaviour in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system

Brain Res.

(1970)

S. Weiss et al.

Is there a neural stem cell in the mammalian forebrain

TINS

(1996)

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^☆: W. M. CowanE. M. ShooterC. F. StevensR. F. Thompson, Eds.

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Regular ArticleLong-Term Survival of Human Central Nervous System Progenitor Cells Transplanted into a Rat Model of Parkinson's Disease☆

Abstract

Brain Res.

Semin. Neurosci.

Neurobiol. Dis.

TIG

FEBS Lett.

Methods Neurosci.

Cell Transplant.

Exp. Neurol.

Neurobiol. Dis.

Exp. Neurol.

Mol. Cell. Neurosci.

Neuroscience

Neurosci. Res.

Brain Res.

Dev. Biol.

Prog. Brain Res.

Neuron

Dev. Brain Res.

Exp. Neurol.

TINS

Brain Res.

TINS

Regular Article
Long-Term Survival of Human Central Nervous System Progenitor Cells Transplanted into a Rat Model of Parkinson's Disease☆