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There is More to a Lipid than just Being a Fat: Sphingolipid-Guided Differentiation of Oligodendroglial Lineage from Embryonic Stem Cells

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Abstract

Dr. Robert K. Yu’s research showed for the first time that the composition of glycosphingolipids is tightly regulated during embryo development. Studies in our group showed that the glycosphingolipid precursor ceramide is also critical for stem cell differentiation and apoptosis. Our new studies suggest that ceramide and its derivative, sphingosine-1-phosphate (S1P), act synergistically on embryonic stem (ES) cell differentiation. When using neural precursor cells (NPCs) derived from ES cells for transplantation, residual pluripotent stem (rPS) cells pose a significant risk of tumor formation after stem cell transplantation. We show here that rPS cells did not express the S1P receptor S1P1, which left them vulnerable to ceramide or ceramide analog (N-oleoyl serinol or S18)-induced apoptosis. In contrast, ES cell-derived NPCs expressed S1P1 and were protected in the presence of S1P or its pro-drug analog FTY720. Consistent with previous studies, FTY720-treated NPCs differentiated predominantly toward oligodendroglial lineage as tested by the expression of the oligodendrocyte precursor cell (OPC) markers Olig2 and O4. As the consequence, a combined administration of S18 and FTY720 to differentiating ES cells eliminated rPS cells and promoted oligodendroglial differentiation. In addition, we show that this combination promoted differentiation of ES cell-derived NPCs toward oligodendroglial lineage in vivo after transplantation into mouse brain.

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Abbreviations

aPKC:

Atypical PKC

EB:

Embryoid body

EBC:

EB-derived cell

ES:

Embryonic stem

iOPC:

Induced oligodendrocyte precursor cell

MBP:

Myelin basic protein

NP:

Neural progenitor

NPC:

Neural precursor cell

OPC:

Oligodendrocyte precursor cell

PAR-4:

Prostate apoptosis response 4

rPS:

Residual pluripotent stem

S1P:

Sphingosine-1-phoshate

S18:

N-oleoyl serinol

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Acknowledgments

This work was supported in part by the NIH grants R01AG034389 and R01NS046835 to EB. The author also acknowledges institutional support (under directorship of Dr. Lin Mei) at the Medical College of Georgia/Georgia Health Sciences University, Augusta, GA. We are thankful to the Imaging Core Facility (under directorship of Dr. Paul McNeil) for assistance with confocal microscopy.

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  1. Program in Developmental Neurobiology, Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia/Georgia Health Sciences University, 1120 15th Street Room CA4012, Augusta, GA, 30912, USA

    Erhard Bieberich

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  1. Erhard Bieberich
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Correspondence to Erhard Bieberich.

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Special Issue: In Honor of Dr. Robert Yu.

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Bieberich, E. There is More to a Lipid than just Being a Fat: Sphingolipid-Guided Differentiation of Oligodendroglial Lineage from Embryonic Stem Cells. Neurochem Res 36, 1601–1611 (2011). https://doi.org/10.1007/s11064-010-0338-5

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