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Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival

Abstract

During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5–7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS.

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Abbreviations

CNS:

Central nervous system

OPCs:

Oligodendrocyte precursor cells

MS:

Multiple sclerosis

PDE:

Phosphodiesterase

cAMP:

3’-5’-cyclic adenosine monophosphate

PKA:

Protein kinase A

CREB:

cAMP response element-binding protein

DIV:

Days in vitro

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Acknowledgments

We thank Dr. Jose Angel Rodríguez Alfaro, Dr. Javier Mazarío, I. Machín, R. Lebrón, I. Sánchez and J. Sarmentero for technical support. This work was supported by grants from the Spanish Ministerio de Economía y Competitividad––MINECO (SAF2009–07842, SAF2012–40023 ADE10–0010, RD07–0060–2007, RD12–0032–12, partially supported by F.E.D.E.R.-European Union “Una manera de hacer Europa”) and the Fundación Eugenio Rodríguez Pascual (Spain) to F.dC,, MINECO (SAF2009–13015 and RD07/0060/0015, partially supported by F.E.D.E.R.-European Union “Una manera de hacer Europa”-) to A.M. and the Spanish Institute of Health-ISCIII (PS09/02116) to J.P. EM.M-R. is a recipient of a predoctoral fellowship from the MINECO FPI program (associated to SAF2009–07842). A.B. holds a postdoctoral contract funded by the “Sara Borrell” program of the FIS-ISCIII/Spanish Ministry of Health. M.R and V.P. were recipients of a pre-doctoral fellowship from the CSIC (JAE program). F.dC. is on contract to SESCAM.

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The authors declare no conflicts of interest.

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Correspondence to A. Bribián or F. de Castro.

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18_2013_1340_MOESM1_ESM.jpg

Supplementary Figure 1: Cultures are enriched in OPCs. Low-magnification immunofluorescence images of PDGFRα cells after 1 DIV isolated from P0 brains (a-c), P15 brains (d-f) and human biopsies (g-i). (j) Plot show the quantification of the percentage of OPCs, identified as PDGFRα+ cells after 1DIV, respect to the total number of cells. Scale bars are 50 µm in a-i. (JPEG 1741 kb)

18_2013_1340_MOESM2_ESM.jpg

Supplementary Figure 2: Every OPC expresses PDE7. (a-h) Low-magnification immunofluorescence images of PDE7A/PDGFRα (a-c) or PDE7B/PDGFRα (e-g) double-labeled P0 derived OPCs to show how both PDE7 isoforms were expressed by almost every OPC (see text), after 1 DIV in differentiation medium. In these pictures, several OPCs per field are observed, while in Figure 1 we show individual cells for illustration purposes. (d,h) shown immunocitochemistry without primary antibodies. (i-p) Low-magnification immunofluorescence images of PDE7A/PDGFRα (i-k) or PDE7B/PDGFRα (m-o) double-labeled P15 derived OPCs in similar conditions as P0 OPC cultures, with similar results. (l,p) shown immunocitochemistry with our primary antibodies. Scale bars are 25 µm in a-p. (JPEG 1421 kb)

18_2013_1340_MOESM3_ESM.jpg

Supplementary Figure 3: Kinetics of PDE7-promoted oligodendroglial differentiation and PDE expression in oligodendroglial lineage. (a) Quantification of pre-oligodendrocytes after 2, 3, 5 and 7DIV. The number of CNPase/Olig2+ cells was higher since the second day of culture until the fifth in the presence of both new PDE7 inhibitors. (b) Plot shown the measurement of fluorescence intensity in purified OPCs cultures immunostained for anti-PDE7A, PDE7B, PDE4B and PDE4D antibodies. It is remarkable that no differences in the expression of PDE7 were found along the days in culture for the oligodendrocyte lineage, although there is a significant difference in the PDE4B expression between the first and the other days in culture. Values are given as mean ± SEM and the results of ANOVA on Ranks are represented as *; P<0.05, **; P<0.01 and ***; P<0.001. (JPEG 487 kb)

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Medina-Rodríguez, E.M., Arenzana, F.J., Pastor, J. et al. Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival. Cell. Mol. Life Sci. 70, 3449–3462 (2013). https://doi.org/10.1007/s00018-013-1340-2

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  • DOI: https://doi.org/10.1007/s00018-013-1340-2

Keywords

  • PDE7 inhibitors
  • Oligodendrocyte differentiation
  • Multiple sclerosis