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Heterogeneity of the Endocannabinoid System Between Cerebral Cortex and Spinal Cord Oligodendrocytes

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Abstract

In the last years, regional differences have been reported between the brain and spinal cord oligodendrocytes, which should be considered when designing therapeutic strategies for myelin repair. Promising targets to achieve myelin restoration are the different components of the endocannabinoid system (ECS) that modulate oligodendrocyte biology, but almost all studies have been focused on brain-derived cells. Therefore, we compared the ECS between the spinal cord and cerebral cortex-derived oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (OLs). Cells from both regions express synthesizing and degrading enzymes for the endocannabinoid 2-arachidonoylglycerol, and degrading enzymes increase with maturation, more notably in the spinal cord (monoglyceride lipase-MGLL, alpha/beta hydrolase domain-containing 6-ABHD6, and alpha/beta hydrolase domain-containing 12-ABHD12). In addition, spinal cord OPCs express higher levels of the synthesizing enzymes diacylglycerol lipases alpha (DAGLA) and beta (DAGLB) than cortical ones, DAGLA reaching statistical significance. Cells from both the cortex and spinal cord express low levels of NAEs synthesizing enzymes, except for the glycerophosphodiester phosphodiesterase 1 (GDE-1) but high levels of the degrading enzyme fatty acid amidohydrolase (FAAH) that increases with maturation. Finally, cells from both regions show similar levels of CB1 receptor and GPR55, but spinal cord-derived cells show significantly higher levels of transient receptor potential cation channel V1 (TRPV1) and CB2. Overall, our results show that the majority of the ECS components could be targeted in OPCs and OLs from both the spinal cord and brain, but regional heterogeneity has to be considered for DAGLA, MGLL, ABHD6, ABHD12, GDE1, CB2, or TRPV1.

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Acknowledgments

We thank Drs. Jose Ángel Rodriguez Alfaro and Javier Mazarío (Microscopy Facilities at the Hospital Nacional de Paraplejicos) for assistance with image acquisition and processing and María del Mar del Cerro for her outstanding technical assistance in the laboratory.

Funding

This work was funded by the Ministry of Science, Innovation, and Universities of Spain, Grant ID SAF2015-69927 (co-funded by FEDER-European Union) to EMH and DGO.

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Authors and Affiliations

  1. Laboratory of Neuroinflammation (lab i2 06), Hospital Nacional de Paraplejicos-SESCAM, Finca La Peraleda s/n, 45071, Toledo, Spain

    R. Moreno-Luna, P. F. Esteban, B. Paniagua-Torija, A. Arevalo-Martin, D. Garcia-Ovejero & E. Molina-Holgado

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  1. R. Moreno-Luna
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  2. P. F. Esteban
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  3. B. Paniagua-Torija
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Correspondence to D. Garcia-Ovejero or E. Molina-Holgado.

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D. Garcia-Ovejero and E. Molina-Holgado should be considered joint senior and corresponding authors.

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Supplementary Fig. 1

High yield cultures are required to obtain enough number of oligodendrocyte cells without using high number of animals. (A) A low number of cells are recovered after trypsin digestion of a single cerebral cortex or spinal cord from a P0 neonatal rat pup. Specially, ten times less cells are obtained from a single spinal cord than from a single cerebral cortex of one animal for the initial mixed cell culture in the classical protocol (PNG 111 kb)

High Resolution Image (TIFF 297 kb)

Supplementary Fig. 2

Myelination progress of dorsal root ganglion cells cocultured with spinal or cortical derived OPCs. (A, B) After 12 days of co-culture, MBP+ OLs (green) show ramified morphologies both in cortex and spinal derived cells, not fully enwrapping Neurofilament+ axons (red), except in occasional cells in spinal cord derived cultures (not shown). (C) After 19 days, occasional myelinating cells with several parallel processes enwrapping axons can be found in cortical derived OPCs, whereas at the same time point (19 days) these cells are frequently found in spinal cord derived cells (D). (E) High frequency of MBP+ myelinating cells similar to that found in spinal cord at 19 days can be found in cortical derived cells at later time points (27 days). Spinal cord derived OPC-DRG cocultures were not maintained beyond 19 days since extensive myelination was already assessed at that time point. Scale bars: 100 μm (JPEG 3861 kb)

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Moreno-Luna, R., Esteban, P.F., Paniagua-Torija, B. et al. Heterogeneity of the Endocannabinoid System Between Cerebral Cortex and Spinal Cord Oligodendrocytes. Mol Neurobiol 58, 689–702 (2021). https://doi.org/10.1007/s12035-020-02148-1

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