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Involvement of Wnt7a in the role of M2c microglia in neural stem cell oligodendrogenesis

Involvement of Wnt7a in the role of M2c microglia in neural stem cell oligodendrogenesis
Involvement of Wnt7a in the role of M2c microglia in neural stem cell oligodendrogenesis

BACKGROUND: The participation of microglia in CNS development and homeostasis indicate that these cells are pivotal for the regeneration that occurs after demyelination. The clearance of myelin debris and the inflammatory-dependent activation of local oligodendrocyte progenitor cells in a demyelinated lesion is dependent on the activation of M2c microglia, which display both phagocytic and healing functions. Emerging interest has been raised about the role of Wnt/β-catenin signaling in oligodendrogenesis and myelination. Besides, cytokines and growth factors released by microglia can control the survival, proliferation, migration, and differentiation of neural stem cells (NSCs), contributing to remyelination through the oligodendrocyte specification of this adult neurogenic niche.

METHODS: TMEV-IDD model was used to study the contribution of dorsal SVZ stem cells to newly born oligodendrocytes in the corpus callosum following demyelination by (i) en-face dorsal SVZ preparations; (ii) immunohistochemistry; and (iii) cellular tracking. By RT-PCR, we analyzed the expression of Wnt proteins in demyelinated and remyelinating corpus callosum. Using in vitro approaches with microglia cultures and embryonic NSCs, we studied the role of purified myelin, Wnt proteins, and polarized microglia-conditioned medium to NSC proliferation and differentiation. One-way ANOVA followed by Bonferroni's post-hoc test, or a Student's t test were used to establish statistical significance.

RESULTS: The demyelination caused by TMEV infection is paralleled by an increase in B1 cells and pinwheels in the dorsal SVZ, resulting in the mobilization of SVZ proliferative progenitors and their differentiation into mature oligodendrocytes. Demyelination decreased the gene expression of Wnt5a and Wnt7a, which was restored during remyelination. In vitro approaches show that Wnt3a enhances NSC proliferation, while Wnt7a and myelin debris promotes oligodendrogenesis from NSCs. As phagocytic M2c microglia secrete Wnt 7a, their conditioned media was found to induce Wnt/β-Catenin signaling in NSCs promoting an oligodendroglial fate.

CONCLUSIONS: We define here the contribution of microglia to Wnt production depending on their activation state, with M1 microglia secreting the Wnt5a protein and M2c microglia secreting Wnt7a. Collectively, our data reveal the role of reparative microglia in NSC oligodendrogenesis with the involvement of Wnt7a.

Microglia, Neural stem cells, Oligodendrogenesis, Subventricular zone, Wnt, β-Catenin
1742-2094
Mecha, Miriam
3cbf6582-afc9-42a8-94a9-27e7d88a098a
Yanguas-Casás, Natalia
c6117a05-6eba-4d2a-a65a-dbcbb554be60
Feliú, Ana
f97a92e7-9058-40be-b085-4e8e233fd129
Mestre, Leyre
d0733ea0-dc95-4bfe-816e-87df87860a90
Carrillo-Salinas, Francisco Javier
25aee3e3-efa9-4ff4-8612-e26133237746
Riecken, Kristoffer
0eca316e-6c54-4cda-80e0-92c571263996
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Guaza, Carmen
da82c3f6-843c-478d-8856-2598b080eee6
Mecha, Miriam
3cbf6582-afc9-42a8-94a9-27e7d88a098a
Yanguas-Casás, Natalia
c6117a05-6eba-4d2a-a65a-dbcbb554be60
Feliú, Ana
f97a92e7-9058-40be-b085-4e8e233fd129
Mestre, Leyre
d0733ea0-dc95-4bfe-816e-87df87860a90
Carrillo-Salinas, Francisco Javier
25aee3e3-efa9-4ff4-8612-e26133237746
Riecken, Kristoffer
0eca316e-6c54-4cda-80e0-92c571263996
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Guaza, Carmen
da82c3f6-843c-478d-8856-2598b080eee6

Mecha, Miriam, Yanguas-Casás, Natalia, Feliú, Ana, Mestre, Leyre, Carrillo-Salinas, Francisco Javier, Riecken, Kristoffer, Gomez-Nicola, Diego and Guaza, Carmen (2020) Involvement of Wnt7a in the role of M2c microglia in neural stem cell oligodendrogenesis. Journal of Neuroinflammation, 17 (1), [88]. (doi:10.1186/s12974-020-01734-3).

Record type: Article

Abstract

BACKGROUND: The participation of microglia in CNS development and homeostasis indicate that these cells are pivotal for the regeneration that occurs after demyelination. The clearance of myelin debris and the inflammatory-dependent activation of local oligodendrocyte progenitor cells in a demyelinated lesion is dependent on the activation of M2c microglia, which display both phagocytic and healing functions. Emerging interest has been raised about the role of Wnt/β-catenin signaling in oligodendrogenesis and myelination. Besides, cytokines and growth factors released by microglia can control the survival, proliferation, migration, and differentiation of neural stem cells (NSCs), contributing to remyelination through the oligodendrocyte specification of this adult neurogenic niche.

METHODS: TMEV-IDD model was used to study the contribution of dorsal SVZ stem cells to newly born oligodendrocytes in the corpus callosum following demyelination by (i) en-face dorsal SVZ preparations; (ii) immunohistochemistry; and (iii) cellular tracking. By RT-PCR, we analyzed the expression of Wnt proteins in demyelinated and remyelinating corpus callosum. Using in vitro approaches with microglia cultures and embryonic NSCs, we studied the role of purified myelin, Wnt proteins, and polarized microglia-conditioned medium to NSC proliferation and differentiation. One-way ANOVA followed by Bonferroni's post-hoc test, or a Student's t test were used to establish statistical significance.

RESULTS: The demyelination caused by TMEV infection is paralleled by an increase in B1 cells and pinwheels in the dorsal SVZ, resulting in the mobilization of SVZ proliferative progenitors and their differentiation into mature oligodendrocytes. Demyelination decreased the gene expression of Wnt5a and Wnt7a, which was restored during remyelination. In vitro approaches show that Wnt3a enhances NSC proliferation, while Wnt7a and myelin debris promotes oligodendrogenesis from NSCs. As phagocytic M2c microglia secrete Wnt 7a, their conditioned media was found to induce Wnt/β-Catenin signaling in NSCs promoting an oligodendroglial fate.

CONCLUSIONS: We define here the contribution of microglia to Wnt production depending on their activation state, with M1 microglia secreting the Wnt5a protein and M2c microglia secreting Wnt7a. Collectively, our data reveal the role of reparative microglia in NSC oligodendrogenesis with the involvement of Wnt7a.

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More information

Accepted/In Press date: 3 February 2020
Published date: 19 March 2020
Keywords: Microglia, Neural stem cells, Oligodendrogenesis, Subventricular zone, Wnt, β-Catenin

Identifiers

Local EPrints ID: 439275
URI: http://eprints.soton.ac.uk/id/eprint/439275
ISSN: 1742-2094
PURE UUID: 883cb6a4-3d12-46be-9b67-87db0dc67e65
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

Catalogue record

Date deposited: 07 Apr 2020 16:32
Last modified: 26 Nov 2021 02:56

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Contributors

Author: Miriam Mecha
Author: Natalia Yanguas-Casás
Author: Ana Feliú
Author: Leyre Mestre
Author: Francisco Javier Carrillo-Salinas
Author: Kristoffer Riecken
Author: Carmen Guaza

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