Smart Drugs for Smarter Stem Cells: Making SENSe (Sphingolipid-Enhanced Neural Stem Cells) of Ceramide

Bieberich, Erhard

doi:10.1159/000111558

Cited by 20 publications

(32 citation statements)

References 188 publications

(205 reference statements)

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“…This hypothesis is consistent with data from our laboratory showing that S1P and FTY720 protect a small population (≤5%) of neural precursor cells (NPCs), termed NPC2, from ceramide-induced apoptosis [358]. We routinely incubate EB-derived cells with S18 to eliminate residual pluripotent stem cells that will form stem cell-derived tumors if they contaminate the stem cell graft [82].…”

Section: Ceramide and S1p: Close Relatives But Conditional Antagonistssupporting

confidence: 82%

“…This method has been recognized as a significant step toward safer stem cell therapy [359][360][361][362]. In contrast to the major population of nestin(+)/ PAR-4(−) NPC1 cells, NPC2 cells maintain the expression of PAR-4 and are eliminated by incubation with S18 [358]. These cells are protected by adding S1P or FTY720, which underlines the importance of S1P as a metabolically derived antagonist of ceramide ( Figure 8B).…”

Section: Ceramide and S1p: Close Relatives But Conditional Antagonistsmentioning

confidence: 97%

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Ceramide signaling in cancer and stem cells

Bieberich

2008

Future Lipidology

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Most of the previous work on the sphingolipid ceramide has been devoted to its function as an apoptosis inducer. Recent studies, however, have shown that in stem cells, ceramide has additional nonapoptotic functions. In this article, ceramide signaling will be reviewed in light of 'systems interface biology': as an interconnection of sphingolipid metabolism, membrane biophysics and cell signaling. The focus will be on the metabolic interconversion of ceramide and sphingomyelin or sphingosine-1-phosphate. Lipid rafts and sphingolipid-induced protein scaffolds will be discussed as a membrane interface for lipid-controlled cell signaling. Ceramide/sphingomyelin and ceramide/ sphingosine-1-phosphate-interdependent cell-signaling pathways are significant for the regulation of cell polarity, apoptosis and/or proliferation, and as novel pharmacologic targets in cancer and stem cells. Keywordsapoptosis; cancer; cell polarity; ceramide; ES cells; lipid rafts; sphingomyelin; sphingosine-1-phosphate Ceramide & its derivatives: from metabolism to cell signalingThe structural core of ceramide is the sphingoid base sphingosine (Figure 1), a lipid that is synthesized from the amino acid serine and the activated fatty acid palmitoyl-CoA (Figure 2). Sphingosine (or sphingenine) was first isolated and characterized by the German pathologist and 'father of neurochemistry ' Johann Ludwig Wilhelm Thudichum (1829-1901 [1,2]. He coined the term sphingolipids, which is derived from 'sphingos', the genitive of Sphinx. In Greek, 'sphingo' means 'to strangle'. According to the legend, a fate of death was meant for everyone who could not solve the riddles posed by the Sphinx. Quite ironically, this is how many sphingolipid researchers may feel when faced with analyzing the function of ceramide. The riddle of ceramide, its function and how it acts as signaling lipid, is far from being solved. To ease our fears when confronted with the Sphinx in sphingolipid biochemistry, a related Greek word, 'sphingein', meaning 'to bind tight', alludes to the possibility of solving the enigma of ceramide by identifying its binding proteins.In addition to ceramide, more than a hundred different sphingolipids are known. The most comprehensive collection of sphingolipids, with respect to their characteristics and structures, can be found at [401], a Webpage supported by the National Institutes of General Medical Sciences [3,4]. Sphingolipids are essential components of cellular membranes and have been (Figure 3) . Among these, their roles as pro-or anti-apoptotic and pro-or anti-proliferative signaling lipids are the most important. Most recently, our group has found that establishment of cell polarity during embryonic development is another biological process regulated by sphingolipids [28]. To define a profile of functions for individual sphingolipids is difficult because of their rapid metabolic interconversion. To add to this predicament, several derivatives of ceramide have functions similar to ceramide itself. Hence, novel techniques are need...

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Section: Ceramide and S1p: Close Relatives But Conditional Antagonistssupporting

confidence: 82%

Section: Ceramide and S1p: Close Relatives But Conditional Antagonistsmentioning

confidence: 97%

Ceramide signaling in cancer and stem cells

Bieberich

2008

Future Lipidology

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“…Ceramide induces the binding of prostate apoptosis response protein 4 (PAR-4) to the atypical protein kinase C [48] , an effect responsible for ceramide-induced apoptosis in cells showing elevated levels of PAR-4. As S1P antagonises ceramide-induced apoptosis [49] , it is likely to protect any cell type with high levels of PAR-4 from ceramide-induced apoptosis [50] . In mESCs, the endogenous levels of ceramide are low, increase upon EB formation until the early phase of NS/PC differentiation and finally decrease during the following steps of neural differentiation [48] .…”

Section: Lpa/s1p Signalling In Mouse Embryonic Stem Cellsmentioning

confidence: 99%

Regulation of Stem Cell Pluripotency and Neural Differentiation by Lysophospholipids

Pitson

Pébay

2009

Neurosignals

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Lysophospholipids are bioactive signalling molecules able to act through the binding of their specific G-protein-coupled receptors to exert pleiotropic effects on a wide range of cells. The most widely studied signalling lysophospholipids are lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). LPA and S1P have been identified to have widespread developmental, physiological and pathological actions in the central nervous system and more recently have been shown to induce biological effects on various stem cell types. This review aims to summarise the current knowledge on LPA and S1P regulation of embryonic and neural stem cell biology.

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“…We have found that teratoma-forming rPS cells do not express the S1P receptor S1P1, which makes them vulnerable to ceramide or S18-induced apoptosis (Bieberich, 2008b(Bieberich, , 2010Bieberich et al, 2004). In contrast, ES cell-derived neural progenitor cells express S1P1.…”

Section: Induction Of Oligodendrocyte Differentiation By S1p and S1p mentioning

confidence: 96%

“…Many studies have shown that even when using similar protocols for the in vitro differentiation of ES cells, transplantation can lead to the formation of teratomas (Baker, 2009;Bieberich, 2008b;Blum &Benvenisty, 2008;Fong et al, 2010;Fujikawa et al, 2005;Lee et al, 2009;Vogel, 2005;. Teratomas are stem cell-derived tumors that are fatal if they grow in the brain or heart.…”

Section: Induction Of Apoptosis In Teratoma-forming Stem Cells By Cermentioning

confidence: 99%