Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Experimental Autoimmune Encephalomyelitis (EAE) Mouse Model
2.2. Human Cell Model of Progenitor Cell Differentiation to Mature Myelin-Producing Oligodendrocytes
2.3. hOPC Supplementation with Fish Oil Mixture
2.4. Lactate Dehydrogenase (LDH) Release Assay
2.5. Immunocytochemical Analysis (ICC)
2.6. RNA Isolation and Total mRNA Concentration Analysis
2.7. Quantitative Real-Time PCR (qRT-PCR)
2.8. Lipid Profiling for Free and Esterified Fatty Acids by Gas Chromatography-Mass Spectrometry (GC/MS)
2.9. Cytokine, Chemokine, and Growth Factor Analysis by Human Cytokine Multiple Profiling Assays
2.10. Statistics
3. Results
3.1. Dysregulated Lipid Composition in EAE Brain in Comparison to Healthy Mouse Brain
3.2. Maturating hOPCs Produce Nervonic Acid
3.3. hOPCs Incorporate and Metabolize Nervonic Acid
3.4. FOM Affects Maturing hOPCs Resulting in Increased Production of Myelin Proteins
3.5. FOM Affects hOPC Production of Cytokines, Chemokines and Growth Factors
3.6. Fish Oil Mixture Promotes hOPC Survival and Prolongs OL Lifespan
4. Discussion
5. Patents
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Lipid Acid | HC [%] | EAE [%] | |
---|---|---|---|
1 | Myristic Acid (C14:0) | n.d. | 0.13 |
2 | Palmitic Acid (C16:0) | 39.48 | 35.14 * |
3 | Palmitoleic Acid (C16:1) | n.d. | 0.65 |
4 | Pentadecanoic Acid (C15:0) | n.d. | 0.58 |
5 | Stearic Acid (C18:0) | 18.85 | 18.06 |
6 | Oleic Acid (C18:1n9c) | 18.19 | 20.30 |
7 | Elaidic Acid (C18:1n9t) | 5.92 | 8.16 * |
8 | Linolelaidic Acid (C18:2n6t) | n.d. | 0.83 |
9 | cis-11-Eicosenoic Acid (C20:1n9) | n.d. | 0.66 |
10 | Arachidonic Acid (C20:4n6) | 1.74 | 5.56 * |
11 | cis-4,7,10,13,16,19-Docosahexaenoic Acid (C22:6n3) | 14.80 | 9.76 * |
12 | Nervonic Acid (C24:1n9) | 1.91 | n.d. * |
Lipid Acid | MO3.13 Cells not Polarized | hOPCs (PMA) | hOPCs (PMA) + FOM | hOPCs (PMA) + LO | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
24 h | 48 h | 72 h | 24 h | 48 h | 72 h | 24 h | 48 h | 72 h | 24 h | 48 h | 72 h | ||
1 | Myristic acid (C14:0) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 1.15# | 1.20# | 1.85# | n.d. | n.d. | 0.12 |
2 | Pentadecanoic acid (C15:0) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 0.13 | n.d. | n.d. | n.d. | n.d. |
3 | Palmitic acid (C16:0) | 9.58 | 9.28 | 8.78 | 3.98 † | 3.66 † | 3.31 † | 8.04 # | 10.04 # | 11.32 # | 5.96 | 3.91 | 4.42 |
4 | Palmitoleic acid (C16:1) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 2.48# | 3.55# | 3.2# | n.d. | n.d. | n.d. |
5 | Heptadeconoic acid (C17:0) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 0.41 | 0.77 | n.d. | n.d. | n.d. | n.d. |
6 | Heptadeconoic acid, 16-methyl | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 0.10 | n.d. | n.d. | n.d. | n.d. |
7 | Cis-10-heptadecenoic acid (C17:1) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 1.67# | n.d. | n.d. | n.d. | n.d. |
8 | Stearic acid (C18:0) | 4.89 | 5.33 | 4.09 | 1.05 † | 1.01 † | 1.34 † | 2.82 # | 2.53 # | 3.65 # | 4.44 # | 2.10 | 2.06 |
9 | Elaidic acid (C18:1n9t) | 0.7 | 3.89 | 2.57 | n.d. | n.d. | n.d. | 22.49 # | 23.12 # | 24.33 # | 17.04 # | 16.81 # | 16.34 # |
10 | Oleic Aaid (C18:1n9c) | 17.98 | 20.21 | 17.65 | 17.87 | 18.90 | 18.86 | n.d. # | n.d. # | n.d. # | n.d. # | n.d. # | 2.24 # |
11 | Linoleic acid (C18:2n6c) | 19.46 | 12.61 | 23.52 | 33.28 † | 30.58 † | 28.28 † | 8.46 # | 1.42 # | 3.47 # | 14.49 # | 28.14 | 25.93 |
12 | Linolelaidic acid (C18:2n6t) | n.d. | n.d. | 2.12 | n.d. | 3.18 | 3.78 | 0.58 # | 0.16 # | n.d. # | n.d. | 2.41 | 0.29 # |
13 | Gamma-Linolenic acid (C18:3n6) | n.d. | n.d. | n.d. | 3.4 † | 2.34 † | 2.38 † | n.d. # | n.d. # | n.d. # | n.d. # | n.d. # | 0.67 # |
14 | Hexadecanoic acid | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 0.03 | n.d. | n.d. | n.d. | n.d. |
15 | Alpha-Linolenic acid (C18:3n3) | n.d. | n.d. | 0.66 | 6.82 † | 5.48 † | 4.58 † | 2.72 # | 0.82 # | n.d. # | 54.71 # | 6.66 | 13.05 # |
16 | Stearidonic acid (C18:4n3) | n.d. | n.d. | n.d. | 0.13 | 0.18 | 0.18 | 0.821 | 1.89 | 3.54 | n.d. | n.d. | n.d. |
17 | Cis-11-Eicosenoic acid (C20:1n9) | 1.05 | 1.35 | 1.19 | 3.74 † | 2.85 † | 2.82 † | 5.11 | 5.46 # | 5.93 # | n.d # | 2.32 | 1.94 |
18 | Cis-11,14,17-Eicosatrienoic acid (C20:3n3) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 0.27 |
19 | Cis-5,8,11,14,17-Eicosapentaenoic acid (C20:5n3) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 9.82 # | 10.53 # | 12.57 # | n.d. | n.d. | n.d. |
20 | Cis-8,11,14-eicosatrienoic acid (C20:3n6) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 0.05 | n.d. | n.d. | n.d. | n.d. |
21 | Arachidic acid (C20:0) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 0.23 | 0.25 | n.d. | 0.64 | 0.51 |
22 | Arachidonic acid (C20:4n6) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 0.45 | 0.94 | 1.21 # | n.d. | n.d. | n.d. |
23 | Behenic acid (C22:0) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 0.09 | n.d. | n.d. | 1.74 # | 0.97 # |
24 | Cetoleic acid (C22:1n11) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 16.02 # | 14.26 # | 13.04 # | 3.34 # | 35.22 # | 30.4 # |
25 | Docosapentaenoic acid | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 1.65 | n.d. | n.d. | n.d. | n.d. |
26 | Cis-13-docosenoic acid (C22:1n9) | 46.38 | 47.27 | 38.74 | 28.51 † | 30.58 † | 32.06 † | n.d. # | n.d. # | n.d. # | n.d. # | n.d. # | n.d. # |
27 | Cis-4,7,10,13,16,19-Docosahexaenoic acid (C22:6n3) | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 5.34 # | 9.18 # | 7.52 # | n.d. | n.d. | n.d. |
28 | Lignoceric acid (C24:0) | n.d. | n.d. | n.d. | 0.39 | 0.17 | 0.38 | n.d. | n.d. | n.d. | n.d. | n.d. | 0.26 |
29 | Nervonic acid (C24:1n9) | n.d. | n.d. | n.d. | 1.32 | 1.31 | 1.44 | 6.78 # | 1.63 # | n.d. # | n.d. # | n.d. # | n.d. # |
30 | Squalene | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 5.78 # | 9.05 # | 8.08 # | n.d. | n.d. | n.d. |
Medium (48 h) | FOM (5%, 48 h) | LO (5%, 48 h) | ||||
---|---|---|---|---|---|---|
MO3.13 | hOPC | MO3.13 | hOPC | MO3.13 | hOPC | |
IL-1β | 0.1 ± 0.04 | 0.3 ± 0.29 | 0.1 ± 0.06 | 0.2 ± 0.16 | 0.1 ± 0.05 | 0.2 ± 0.13 |
IL-1ra | 30.1 ± 13.66 | 40.8 ± 17.97 † | 33.5 ± 17.59 | 40.0 ± 19.94 | 28.3 ± 12.00 | 37.2 ± 18.31 |
IL-2 | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. |
IL-4 | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. |
IL-5 | 6.6 ± 2.90 | 17.3 ± 9.56 † | 6.5 ± 3.55 | 9.9 ± 3.92 # | 11.0 ± 5.44 | 16.0 ± 11.80 |
IL-6 | 5.4 ± 0.99 | 22.9 ± 3.93 † | 4.0 ± 0.79 | 7.1 ± 1.02 # | 4.9 ± 1.11 | 19.6 ± 4.02 |
IL-7 | 13.1 ± 9.81 | 24.5 ± 11.32 † | 10.6 ± 6.61 | 11.0± 5.58 # | 12.0 ± 10.82 | 21.7 ± 15.09 |
IL-8 | 358.4 ± 52.62 | 1102.6 ± 167.59 † | 419.6 ± 59.55 | 651.2 ± 91.05 # | 535.6 ± 84.53 * | 1287.9 ± 192.67 |
IL-9 | 6.1 ± 2.98 | 13.3 ± 9.33 † | 6.1 ± 2.11 | 9.8± 5.57 | 8.1 ± 3.97 | 12.4 ± 9.11 |
IL-10 | 6.6 ± 2.04 | 8.1 ± 3.98 | 6.4 ± 2.62 | 6.2 ± 2.77 | 6.3 ± 2.96 | 5.7 ± 3.99 |
IL-12 | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. |
IL-13 | 1.1 ± 0.88 | 1.7 ± 0.55 | 1.3 ± 0.42 | 1.6 ± 0.71 | 1.2 ± 0.51 | 1.4 ± 0.56 |
IL-15 | 36.4 ± 16.82 | 58.5 ± 17.07 † | 20.7 ± 12.77 * | 9.7 ± 7.88 # | 42.7 ± 21.29 | 53.2 ± 28.67 |
IL-17A | 4.8 ± 2.95 | 7.1 ± 3.56 † | 4.5 ± 2.11 | 4.1 ± 1.46 # | 4.1 ± 3.34 | 7.3 ± 3.86 |
Eotaxin | 54.4 ± 21.33 | 90.9 ± 32.78 † | 36.6 ± 16.73 * | 49.0 ± 20.55 # | 31.4 ± 20.76 * | 72.3 ± 22.51 |
FGF-2 | n.d. | 18.6 ± 4.33 † | 16.9 ± 3.21 * | 40.9± 6.81 # | 14.2 ± 2.77 * | 18.5 ± 2.80 |
G-CSF | 95.9 ± 46.15 | 132.1 ± 52.82 † | 94.0 ± 26.82 | 62.0 ± 12.90 # | 90.1 ± 26.80 | 78.3 ± 21.91 # |
GM-CSF | n.d. | 0.6 ± 0.46 | n.d. | 0.6 ± 0.29 | n.d. | 0.8 ± 0.60 |
IFN-γ | 50.2 ± 12.96 | 110.1 ± 25.44 † | 44.9 ± 22.39 | 54.4 ± 24.86 # | 39.5 ± 15.91 | 72.7 ± 22.55 # |
IP-10 | 33.4 ± 18.80 | 53.4 ± 21.96 † | 44.9 ± 24.62 | 43.7 ± 22,95 | 40.2 ± 18.49 | 46.8 ± 21.88 |
MCP-1 | 1175.4 ± 201.60 | 2105.6 ± 399.63 † | 857.8 ± 142.18 * | 968.2 ± 199.33 # | 976.9 ± 247.78 | 1567.0 ± 451.83 |
MIP-1α | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. |
PDGF-bb | 56.7 ± 17.97 | 82.7 ± 23.55 † | 53.5 ± 10.04 | 79.4 ± 12.18 | 53.6 ± 19.76 | 79.6 ± 21.68 |
MIP-1β | 2.8 ± 1.13 | 6.9 ± 2.99 † | 4.3 ± 2.98 | 5.2 ± 3.08 | 3.6 ± 1.83 | 6.0 ± 2.75 |
RANTES | 16.4 ± 9.33 | 28.3± 9.74 † | 15.4 ± 10.59 | 14.2 ± 9.44 # | 16.1 ± 8.07 | 23.7 ± 12.94 |
TNF | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. |
VEGF | 99.2 ± 21.69 | 139.6 ± 43.80 † | 119.6 ± 28.75 | 227.9 ± 69.43 # | 110.3 ± 41.54 | 140.0 ± 59.43 |
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Lewkowicz, N.; Piątek, P.; Namiecińska, M.; Domowicz, M.; Bonikowski, R.; Szemraj, J.; Przygodzka, P.; Stasiołek, M.; Lewkowicz, P. Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes. Cells 2019, 8, 786. https://doi.org/10.3390/cells8080786
Lewkowicz N, Piątek P, Namiecińska M, Domowicz M, Bonikowski R, Szemraj J, Przygodzka P, Stasiołek M, Lewkowicz P. Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes. Cells. 2019; 8(8):786. https://doi.org/10.3390/cells8080786
Chicago/Turabian StyleLewkowicz, Natalia, Paweł Piątek, Magdalena Namiecińska, Małgorzata Domowicz, Radosław Bonikowski, Janusz Szemraj, Patrycja Przygodzka, Mariusz Stasiołek, and Przemysław Lewkowicz. 2019. "Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes" Cells 8, no. 8: 786. https://doi.org/10.3390/cells8080786
APA StyleLewkowicz, N., Piątek, P., Namiecińska, M., Domowicz, M., Bonikowski, R., Szemraj, J., Przygodzka, P., Stasiołek, M., & Lewkowicz, P. (2019). Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes. Cells, 8(8), 786. https://doi.org/10.3390/cells8080786