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The Journal of Neuroscience, December 1, 2004, 24(48):10786-10795; doi:10.1523/JNEUROSCI.3208-04.2004

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Development/Plasticity/Repair
The Generation of Dopaminergic Neurons by Human Neural Stem Cells Is Enhanced by Bcl-X_L, Both In Vitro and In Vivo

Isabel Liste, Elisa García-García, and Alberto Martínez-Serrano

Center of Molecular Biology Severo Ochoa, Autonomous University of Madrid, 28049 Madrid, Spain

Progress in stem cell biology research is enhancing our ability to generate specific neuron types for basic and applied studies and to design new treatments for neurodegenerative diseases. In the case of Parkinson's disease (PD), alternative human dopaminergic (DAergic) neurons other than primary fetal tissue do not yet exist. One possible source could be human neural stem cells (hNSCs), although the yield in DAergic neurons and their survival are very limited.

View larger version (28K): [in this window] [in a new window]   Figure 2. Transgenic TH overexpression: coexpression of TH and helper genes enhances the number of TH+ hNS1 cells. A, Microphotographs illustrating the increased number of TH+ cells after cotransfection of a TH-coding vector with other vectors coding for BDNF, GDNF, SOD1cit, Bcl-XL, or the empty vector, as a control. Scale bar, 100 µm. B, Quantification of the number of TH+ cells in the cotransfection experiments shown in A (n = 12; four independent samples in each of three separate experimental rounds); #p < 0.0001, Bcl-XL vs all other groups; *p < 0.005, different from the empty vector group (Student's t test).

 
In this study, we found that Bcl-X_L enhances (one-to-two orders of magnitude) the capacity for spontaneous dopaminergic differentiation of hNSCs, which then exceeds that of cultured human ventral mesencephalic tissue. Bcl-X_L also enhanced total neuron generation by hNSCs, but to a lower extent. Neuronal phenotypes other than DA were not affected by Bcl-X_L, indicating an exquisitely specific effect on DAergic neurons. In vivo, grafts of Bcl-X_L-overexpressing hNSCs do generate surviving human TH⁺ neurons in the adult rat 6-OH-dopamine lesioned striatum, something never seen when naive hNSCs were transplanted. Most of the data obtained here in terms of the effects of Bcl-X_L are consistent with an enhanced survival type of mechanism and not supportive of induction, specification, or proliferation of DAergic precursors.

From this in vitro and in vivo evidence, we conclude that enhancing Bcl-X_L expression is important to obtain human DAergic neurons from hNSCs. These findings may facilitate the development of drug-screening and cell-replacement activities to discover new therapeutic strategies for PD.

Key words: human neural stem cells; tyrosine hydroxylase; dopaminergic; Bcl-X_L; Parkinson's disease; SOD; GDNF; BDNF

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Received Oct 16, 2003; revised October 5, 2004; accepted October 8, 2004.

This article has been cited by other articles:

				M. Ekici, M. Hohl, F. Schuit, A. Martinez-Serrano, and G. Thiel Transcription of Genes Encoding Synaptic Vesicle Proteins in Human Neural Stem Cells: CHROMATIN ACCESSIBILITY, HISTONE METHYLATION PATTERN, AND THE ESSENTIAL ROLE OF REST J. Biol. Chem., April 4, 2008; 283(14): 9257 - 9268. [Abstract] [Full Text] [PDF]

				M.-Y. Chang, W. Sun, W. Ochiai, K. Nakashima, S.-Y. Kim, C.-H. Park, J. S. Kang, J.-W. Shim, A-Y. Jo, C.-S. Kang, et al. Bcl-XL/Bax Proteins Direct the Fate of Embryonic Cortical Precursor Cells Mol. Cell. Biol., June 15, 2007; 27(12): 4293 - 4305. [Abstract] [Full Text] [PDF]

				B. Dass, C. W. Olanow, and J. H. Kordower Gene transfer of trophic factors and stem cell grafting as treatments for Parkinson's disease Neurology, May 23, 2006; 66(10_suppl_4): S89 - S103. [Abstract] [Full Text]

				J. M. Savitt, S. S. Jang, W. Mu, V. L. Dawson, and T. M. Dawson Bcl-x Is Required for Proper Development of the Mouse Substantia Nigra J. Neurosci., July 20, 2005; 25(29): 6721 - 6728. [Abstract] [Full Text] [PDF]

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