Prostaglandin EP2 Receptors Mediate Mesenchymal Stromal Cell-Neuroprotective Effects on Dopaminergic Neurons

Abstract

Mesenchymal stromal cells (MSCs) have been shown to have useful properties for cell therapy and have been proposed for treatment of neurodegenerative diseases, including Parkinson’s disease. However, the mechanisms involved in recovering dopaminergic neurons are not clear. The present study aims to evaluate the pathways and molecules involved in the neuroprotective effect of MSCs. We analyzed the viability of dopaminergic cells from different sources in response to conditioned medium derived from bone marrow MSC (MSC-CM). MSC-CM increased the viability of dopaminergic cells of rat and human origins, having both neuroprotective and neurorescue activities against effects of dopaminergic neurotoxin 6-hydroxydopamine. We found that lipid removal, inhibition of the prostaglandin E2 receptor 2 (EP2), and its signaling pathway were able to block the effects of MSC-CM on a pure population of dopaminergic neurons. Moreover, in primary mesencephalic cultures and hiPSC-derived neurons, inhibition of EP2 signaling caused a reduction in the number of dopaminergic neurons obtained in culture. Taken together, our results demonstrate for the first time the involvement of prostaglandin signaling from MSC in dopaminergic neuron survival through EP2 receptors, and suggest new approaches for treatment of Parkinson’s disease.

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Acknowledgements

We thank Dr. Wei-Dong Le for providing the Mes23.5 dopaminergic cell line. We thank Pilar Aldrey, Iria Novoa, and Cristina Gianzo for their technical assistance. Grant sponsors of this work are Spanish Ministry of Economy and Competitiveness (BFU2015-70523), Spanish Ministry of Health (RD12/0019/0020, RD16/0011/0016, and CIBERNED), Galician Government (XUGA and Centro singular de investigación de Galicia acreditación 2016-2019, ED431G/05), and European Regional Development Fund (ERDF).

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Correspondence to José Luis Labandeira-García.

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Research Involving Human Participants and/or Animals

All experiments using animals were carried out in accordance with the European Communities Council Directive 2010/63/EU, Directive 86/609/ EEC and Spanish RD 526/2014, and were approved by the corresponding committee at the University of Santiago de Compostela.

Experiments using human-derived cells were approved by the corresponding committees of the Spanish Advisory Committee for Human Tissue and Cell Donation and Use and of the University of Santiago de Compostela, and authorized by the local government

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Supplementary Fig. 1
figure7

Representative pictures of positive and negative controls for the antibodies CD44 and CD90. A large number of erythrocytes and a few nucleated cells stained with CD44 and Hoechst (A). Cardiac fibroblasts stained with CD90 and Hoechst (B). MSC (C) stained with the same protocol used in (A) and (B), but without primary antibody. This protocol results in no green staining together with Hoechst-positive cellular nuclei (blue). Scale bar, 50 μm (A,C), and 25 μm (B). (GIF 85 kb)

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Parga, J.A., García-Garrote, M., Martínez, S. et al. Prostaglandin EP2 Receptors Mediate Mesenchymal Stromal Cell-Neuroprotective Effects on Dopaminergic Neurons. Mol Neurobiol 55, 4763–4776 (2018). https://doi.org/10.1007/s12035-017-0681-5

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Keywords

  • Prostaglandin
  • Parkinson’s disease
  • Dopaminergic neurons
  • Mesenchymal stromal cells
  • Neuroprotection