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Multipotent Neural Stem Cells from the Adult Tegmentum with Dopaminergic Potential Develop Essential Properties of Functional Neurons

Hermann, Andreas and Maisel, Martina and Wegner, Florian and Liebau, Stefan and Kim, Dong-Wook and Gerlach, Manfred and Schwarz, Johannes and Kim, Kwang-Soo and Storch, Alexander (2006) Multipotent Neural Stem Cells from the Adult Tegmentum with Dopaminergic Potential Develop Essential Properties of Functional Neurons. Stem Cells, 24 (4). pp. 949-964. ISSN 1549-4918. https://resolver.caltech.edu/CaltechAUTHORS:20170408-162524996

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Abstract

Neurogenesis in the adult brain occurs within the two principal neurogenic regions: the hippocampus and the subventricular zone of the lateral ventricles. The occurrence of adult neurogenesis in non-neurogenic regions, including the midbrain, remains controversial, but isolation of neural stem cells (NSCs) from several parts of the adult brain, including the substantia nigra, has been reported. Nevertheless, it is unclear whether adult NSCs do have the capacity to produce functional dopaminergic neurons, the cell type lost in Parkinson's disease. Here, we describe the isolation, expansion, and in vitro characterization of adult mouse tegmental NSCs (tNSCs) and their differentiation into functional nerve cells, including dopaminergic neurons. These tNSCs showed neurosphere formation and expressed high levels of early neuroectodermal markers, such as the proneural genes NeuroD1, Neurog2, and Olig2, the NSC markers Nestin and Musashi1, and the proliferation markers Ki67 and BrdU (5-bromo-2-deoxyuridine). The cells showed typical propidium iodide–fluorescence-activated cell sorting analysis of slowly dividing cells. In the presence of selected growth factors, tNSCs differentiated into astroglia, oligodendroglia, and neurons expressing markers for cholinergic, GABAergic, and glutamatergic cells. Electrophysiological analyses revealed functional properties of mature nerve cells, such as tetrodotoxin-sensitive sodium channels, action potentials, as well as currents induced by GABA (γ-aminobutyric acid), glutamate, and NMDA (N-methyl-d-aspartate). Clonal analysis demonstrated that individual NSCs retain the capacity to generate both glia and neurons. After a multistep differentiation protocol using co-culture conditions with PA6 stromal cells, a small number of cells acquired morphological and functional properties of dopaminergic neurons in culture. Here, we demonstrate the existence of adult tNSCs with functional neurogenic and dopaminergic potential, a prerequisite for future endogenous cell replacement strategies in Parkinson's disease.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1634/stemcells.2005-0192DOIArticle
ORCID:
AuthorORCID
Kim, Dong-Wook0000-0002-5497-5853
Additional Information:© 2006 AlphaMed Press. Received April 26, 2005; accepted for publication December 9, 2005; first published online in STEM CELLS EXPRESS December 22, 2005. We thank Oana M. Popa, Snezana Maljevic, and Holger Lerche for fruitful discussions; and Thomas Lenk for technical assistance. This work was supported in part by grants from the Interdisciplinary Center for Clinical Research Ulm (Interdiszlplinäres Zentrum für Klinische Forschung [IZKF] Ulm [Project D6] to A.S. and the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung [BMBF]; Polish-German Cooperation in Neuroscience Program) to A.S. A.H. was supported by an IZKF fellowship as a member of the graduate college GRK460, Ulm. The authors indicate no potential conflicts of interest.
Funders:
Funding AgencyGrant Number
Interdiszlplinäres Zentrum für Klinische ForschungUNSPECIFIED
Bundesministerium für Bildung und Forschung (BMBF)UNSPECIFIED
Subject Keywords:Adult neurogenesis; Neural stem cells; Dopaminergic differentiation; Parkinson's disease; Electrophysiology; Neuroregeneration
Issue or Number:4
Record Number:CaltechAUTHORS:20170408-162524996
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170408-162524996
Official Citation:Hermann, A., Maisel, M., Wegner, F., Liebau, S., Kim, D.-W., Gerlach, M., Schwarz, J., Kim, K.-S. and Storch, A. (2006), Multipotent Neural Stem Cells from the Adult Tegmentum with Dopaminergic Potential Develop Essential Properties of Functional Neurons. STEM CELLS, 24: 949–964.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76181
Collection:CaltechAUTHORS
Deposited By: 1Science Import
Deposited On:26 Jul 2017 23:21
Last Modified:07 Jul 2020 20:23

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