Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery in Parkinsonian mice

Yi Fang Cui, Gunnar Hargus, Jinchong Xu, Janinne Sylvie Schmid, Yan Qin Shen, Markus Glatzel, Melitta Schachner, Christian Bernreuther

Research output: Contribution to journalArticle

Abstract

Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease, and the most common movement disorder. Drug treatment and deep brain stimulation can ameliorate symptoms, but the progressive degeneration of dopaminergic neurons in the substantia nigra eventually leads to severe motor dysfunction. The transplantation of stem cells has emerged as a promising approach to replace lost neurons in order to restore dopamine levels in the striatum and reactivate functional circuits. We have generated substrate-adherent embryonic stem cell-derived neural aggregates overexpressing the neural cell adhesion molecule L1, because it has shown beneficial functions after central nervous system injury. L1 enhances neurite outgrowth and neuronal migration, differentiation and survival as well as myelination. In a previous study, L1 was shown to enhance functional recovery in a mouse model of Huntington's disease. In another study, a new differentiation protocol for murine embryonic stem cells was established allowing the transplantation of stem cell-derived neural aggregates consisting of differentiated neurons and radial glial cells into the lesioned brain. In the present study, this embryonic stem cell line was engineered to overexpress L1 constitutively at all stages of differentiation and used to generate stem cell-derived neural aggregates. These were monitored in their effects on stem cell survival and differentiation, rescue of endogenous dopaminergic neurons and ability to influence functional recovery after transplantation in an animal model of Parkinson's disease. Female C57BL/6J mice (2 months old) were treated with the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intraperitoneally to deplete dopaminergic neurons selectively, followed by unilateral transplantation of stem cell-derived neural aggregates into the striatum. Mice grafted with L1 overexpressing stem cell-derived neural aggregates showed better functional recovery when compared to mice transplanted with wild-type stem cell-derived neural aggregates and vehicle-injected mice. Morphological analysis revealed increased numbers and migration of surviving transplanted cells, as well as increased numbers of dopaminergic neurons, leading to enhanced levels of dopamine in the striatum ipsilateral to the grafted side in L1 overexpressing stem cell-derived neural aggregates, when compared to wild-type stem cell-derived neural aggregates. The striatal levels of gamma-aminobutyric acid were not affected by L1 overexpressing stem cell-derived neural aggregates. Furthermore, L1 overexpressing, but not wild-type stem cell-derived neural aggregates, enhanced survival of endogenous host dopaminergic neurons after transplantation adjacent to the substantia nigra pars compacta. Thus, L1 overexpressing stem cell-derived neural aggregates enhance survival and migration of transplanted cells, differentiation into dopaminergic neurons, survival of endogenous dopaminergic neurons, and functional recovery after syngeneic transplantation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)189-204
Number of pages16
JournalBrain
Volume133
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

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Neural Stem Cells
Embryonic Stem Cells
Dopaminergic Neurons
Stem Cell Transplantation
Parkinson Disease
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Cell Differentiation
Dopamine
Transplantation
Neural Cell Adhesion Molecule L1
Isogeneic Transplantation
Ependymoglial Cells
Nervous System Trauma
Neurons
Corpus Striatum
Aptitude
Deep Brain Stimulation
Huntington Disease
Movement Disorders
Substantia Nigra

Keywords

  • Dopaminergic neurons
  • Embryonic stem cells
  • L1
  • MPTP
  • Neural aggregates

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Cui, Y. F., Hargus, G., Xu, J., Schmid, J. S., Shen, Y. Q., Glatzel, M., ... Bernreuther, C. (2010). Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery in Parkinsonian mice. Brain, 133(1), 189-204. https://doi.org/10.1093/brain/awp290

Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery in Parkinsonian mice. / Cui, Yi Fang; Hargus, Gunnar; Xu, Jinchong; Schmid, Janinne Sylvie; Shen, Yan Qin; Glatzel, Markus; Schachner, Melitta; Bernreuther, Christian.

In: Brain, Vol. 133, No. 1, 01.2010, p. 189-204.

Research output: Contribution to journalArticle

Cui, YF, Hargus, G, Xu, J, Schmid, JS, Shen, YQ, Glatzel, M, Schachner, M & Bernreuther, C 2010, 'Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery in Parkinsonian mice', Brain, vol. 133, no. 1, pp. 189-204. https://doi.org/10.1093/brain/awp290
Cui, Yi Fang ; Hargus, Gunnar ; Xu, Jinchong ; Schmid, Janinne Sylvie ; Shen, Yan Qin ; Glatzel, Markus ; Schachner, Melitta ; Bernreuther, Christian. / Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery in Parkinsonian mice. In: Brain. 2010 ; Vol. 133, No. 1. pp. 189-204.
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