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Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain

Abstract

Human embryonic stem (hES) cells provide a potentially unlimited cell source for regenerative medicine. Recently, differentiation strategies were developed to direct hES cells towards neural fates in vitro. However, the interaction of hES cell progeny with the adult brain environment remains unexplored. Here we report that hES cell–derived neural precursors differentiate into neurons, astrocytes and oligodendrocytes in the normal and lesioned brain of young adult rats and migrate extensively along white matter tracts. The differentiation and migration behavior of hES cell progeny was region specific. The hES cell–derived neural precursors integrated into the endogenous precursor pool in the subventricular zone, a site of persistent neurogenesis. Like adult neural stem cells, hES cell–derived precursors traveled along the rostral migratory stream to the olfactory bulb, where they contributed to neurogenesis. We found no evidence of cell fusion, suggesting that hES cell progeny are capable of responding appropriately to host cues in the subventricular zone.

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Figure 1: In vitro derivation of EGFP+ neural precursors from human ES cells.
Figure 2: Transplantation of hES-derived neural precursors into the striatum of the young adult rodent brain.
Figure 3: Kinetic analysis of human cell migration from the SVZ to the olfactory bulb post transplantation into the SVZ.
Figure 4: Camera lucida drawings of representative coronal sections at the level of proximal rostral migratory stream (RMS), distal RMS and olfactory bulb on days 1, 4 and 28 after BrdU injection.

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Acknowledgements

We thank R. McKay for the nestin antibody, S. Anderson and J. Rubenstein for the Dlx2 antibody and M. Leversha for the DNA probes and assistance with GISH. Supported by the National Institute of Neurological Disorders and Stroke, NIH, R21NS046045, the Michael W. McCarthy Foundation, the M.J. Fox Foundation, and the Kinetics Foundation. M.S. is supported by NIH grants HL57612 and CA08748.

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Correspondence to Viviane Tabar.

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Supplementary information

Supplementary Fig. 1

GFP and hNA colocalization. (PDF 207 kb)

Supplementary Fig. 2

Three-dimensional reconstruction of 0.5 μm confocal sections of human cells in vivo. (PDF 298 kb)

Supplementary Fig. 3

Immunohistochemical profile of hES cell progeny in vivo. (PDF 228 kb)

Supplementary Fig. 4

Split multichannel images of the confocal panels shown in Supplementary Figure 2. (PDF 306 kb)

Supplementary Fig. 5

No evidence of cell fusion. (PDF 131 kb)

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Tabar, V., Panagiotakos, G., Greenberg, E. et al. Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nat Biotechnol 23, 601–606 (2005). https://doi.org/10.1038/nbt1088

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