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N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation.

ABSTRACT: Docosahexaenoic acid (DHA) has been shown to promote neuronal differentiation of neural stem cells (NSCs) in vivo and in vitro. Previously, we found that N-docosahexaenoylethanolamine (synaptamide), an endogenous DHA metabolite with an endocannabinoid-like structure, promotes neurite growth, synaptogenesis, and synaptic function. In this study, we demonstrate that synaptamide potently induces neuronal differentiation of NSCs. Differentiating NSCs were capable of synthesizing synaptamide from DHA. Treatment of NSCs with synaptamide at low nanomolar concentrations significantly increased the number of MAP2 and Tuj-1-positive neurons with concomitant induction of protein kinase A (PKA)/cAMP response element binding protein (CREB) phosphorylation. Conversely, PKA inhibitors or PKA knockdown abolished the synaptamide-induced neuronal differentiation of NSCs. URB597, a fatty acid amide hydrolase (FAAH) inhibitor, elevated the level of DHA-derived synaptamide and further potentiated the DHA- or synaptamide-induced neuronal differentiation of NSCs. Similarly, NSCs obtained from FAAH KO mice exhibited greater capacity to induce neuronal differentiation in response to DHA or synaptamide compared to the wild type NSCs. Neither synaptamide nor DHA affected NSC differentiation into GFAP-positive glia cells. These results suggest that endogenously produced synaptamide is a potent mediator for neurogenic differentiation of NSCs acting through PKA/CREB activation.

SUBMITTER: Rashid MA

PROVIDER: S-EPMC3775276 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation.

Rashid Mohammad A MA Katakura Masanori M Kharebava Giorgi G Kevala Karl K Kim Hee-Yong HY

Journal of neurochemistry 20130513 6

Docosahexaenoic acid (DHA) has been shown to promote neuronal differentiation of neural stem cells (NSCs) in vivo and in vitro. Previously, we found that N-docosahexaenoylethanolamine (synaptamide), an endogenous DHA metabolite with an endocannabinoid-like structure, promotes neurite growth, synaptogenesis, and synaptic function. In this study, we demonstrate that synaptamide potently induces neuronal differentiation of NSCs. Differentiating NSCs were capable of synthesizing synaptamide from DHA ...[more]

PMID: 23570577

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Project description:Tethered growth factors offer exciting new possibilities for guiding stem cell behavior. However, many of the current methods present substantial drawbacks which can limit their application and confound results. In this work, we developed a new method for the site-specific covalent immobilization of azide-tagged growth factors and investigated its utility in a model system for guiding neural stem cell (NSC) behavior. An engineered interferon-? (IFN-?) fusion protein was tagged with an N-terminal azide group, and immobilized to two different dibenzocyclooctyne-functionalized biomimetic polysaccharides (chitosan and hyaluronan). We successfully immobilized azide-tagged IFN-? under a wide variety of reaction conditions, both in solution and to bulk hydrogels. To understand the interplay between surface chemistry and protein immobilization, we cultured primary rat NSCs on both materials and showed pronounced biological effects. Expectedly, immobilized IFN-? increased neuronal differentiation on both materials. Expression of other lineage markers varied depending on the material, suggesting that the interplay of surface chemistry and protein immobilization plays a large role in nuanced cell behavior. We also investigated the bioactivity of immobilized IFN-? in a 3D environment in vivo and found that it sparked the robust formation of neural tube-like structures from encapsulated NSCs. These findings support a wide range of potential uses for this approach and provide further evidence that adult NSCs are capable of self-organization when exposed to the proper microenvironment.For stem cells to be used effectively in regenerative medicine applications, they must be provided with the appropriate cues and microenvironment so that they integrate with existing tissue. This study explores a new method for guiding stem cell behavior: covalent growth factor tethering. We found that adding an N-terminal azide-tag to interferon-? enabled stable and robust Cu-free 'click' immobilization under a variety of physiologic conditions. We showed that the tagged growth factors retained their bioactivity when immobilized and were able to guide neural stem cell lineage commitment in vitro. We also showed self-organization and neurulation from neural stem cells in vivo. This approach will provide another tool for the orchestration of the complex signaling events required to guide stem cell integration.

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N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation.

Publications

N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation.

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