Astrocyte-Derived Exosomes Treated With a Semaphorin 3A Inhibitor Enhance Stroke Recovery via Prostaglandin D2 Synthase

Kenichiro Hira, Yuji Ueno, Ryota Tanaka, Nobukazu Miyamoto, Kazuo Yamashiro, Toshiki Inaba, Takao Urabe, Hideyuki Okano, Nobutaka Hattori

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background and Purpose- Exosomes play a pivotal role in neurogenesis. In the peri-infarct area after stroke, axons begin to regenerate but are inhibited by astrocyte scar formation. The direct effect and underlying molecular mechanisms of astrocyte-derived exosomes on axonal outgrowth after ischemia are not known. Methods- Using a semaphorin 3A (Sema3A) inhibitor, we explored neuronal signaling during axonal outgrowth after ischemia in rats subjected to middle cerebral artery occlusion and in cultured cortical neurons challenged with oxygen-glucose deprivation. Furthermore, we assessed whether this inhibitor suppressed astrocyte activation and regulated astrocyte-derived exosomes to enhance axonal outgrowth after ischemia. Results- In rats subjected to middle cerebral artery occlusion, we administered a Sema3A inhibitor into the peri-infarct area from 7 to 21 days after occlusion. We found that phosphorylated high-molecular weight neurofilament-immunoreactive axons were increased, glial fibrillary acidic protein-immunoreactive astrocytes were decreased, and functional recovery was promoted at 28 days after middle cerebral artery occlusion. In cultured neurons, the Sema3A inhibitor decreased Rho family GTPase 1, increased R-Ras, which phosphorylates Akt and glycogen synthase kinase 3β (GSK-3β), selectively increased phosphorylated GSK-3β in axons, and thereby enhanced phosphorylated high-molecular weight neurofilament-immunoreactive axons after oxygen-glucose deprivation. In cultured astrocytes, the Sema3A inhibitor suppressed activation of astrocytes induced by oxygen-glucose deprivation. Exosomes secreted from ischemic astrocytes treated with the Sema3A inhibitor further promoted axonal elongation and increased prostaglandin D2 synthase expression on microarray analysis. GSK-3β+ and prostaglandin D2 synthase+ neurons were robustly increased after treatment with the Sema3A inhibitor in the peri-infarct area. Conclusions- Neuronal Rho family GTPase 1/R-Ras/Akt/GSK-3β signaling, axonal GSK-3β expression, and astrocyte-derived exosomes with prostaglandin D2 synthase expression contribute to axonal outgrowth and functional recovery after stroke.

Original languageEnglish
Pages (from-to)2483-2494
Number of pages12
JournalStroke
Volume49
Issue number10
DOIs
Publication statusPublished - 2018 Oct 1

Fingerprint

prostaglandin R2 D-isomerase
Semaphorin-3A
Exosomes
Astrocytes
Stroke
Glycogen Synthase Kinase 3
Axons
Middle Cerebral Artery Infarction
rho GTP-Binding Proteins
Ischemia
Intermediate Filaments
Oxygen
Neurons
Glucose
Molecular Weight
Glial Fibrillary Acidic Protein
Neurogenesis
Microarray Analysis

Keywords

  • astrocytes
  • axon
  • exosomes
  • neurons
  • semaphorin 3A
  • stroke

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialised Nursing

Cite this

Hira, K., Ueno, Y., Tanaka, R., Miyamoto, N., Yamashiro, K., Inaba, T., ... Hattori, N. (2018). Astrocyte-Derived Exosomes Treated With a Semaphorin 3A Inhibitor Enhance Stroke Recovery via Prostaglandin D2 Synthase. Stroke, 49(10), 2483-2494. https://doi.org/10.1161/STROKEAHA.118.021272

Astrocyte-Derived Exosomes Treated With a Semaphorin 3A Inhibitor Enhance Stroke Recovery via Prostaglandin D2 Synthase. / Hira, Kenichiro; Ueno, Yuji; Tanaka, Ryota; Miyamoto, Nobukazu; Yamashiro, Kazuo; Inaba, Toshiki; Urabe, Takao; Okano, Hideyuki; Hattori, Nobutaka.

In: Stroke, Vol. 49, No. 10, 01.10.2018, p. 2483-2494.

Research output: Contribution to journalArticle

Hira, K, Ueno, Y, Tanaka, R, Miyamoto, N, Yamashiro, K, Inaba, T, Urabe, T, Okano, H & Hattori, N 2018, 'Astrocyte-Derived Exosomes Treated With a Semaphorin 3A Inhibitor Enhance Stroke Recovery via Prostaglandin D2 Synthase', Stroke, vol. 49, no. 10, pp. 2483-2494. https://doi.org/10.1161/STROKEAHA.118.021272
Hira, Kenichiro ; Ueno, Yuji ; Tanaka, Ryota ; Miyamoto, Nobukazu ; Yamashiro, Kazuo ; Inaba, Toshiki ; Urabe, Takao ; Okano, Hideyuki ; Hattori, Nobutaka. / Astrocyte-Derived Exosomes Treated With a Semaphorin 3A Inhibitor Enhance Stroke Recovery via Prostaglandin D2 Synthase. In: Stroke. 2018 ; Vol. 49, No. 10. pp. 2483-2494.
@article{08026ab777aa486690f536c287d57d46,
title = "Astrocyte-Derived Exosomes Treated With a Semaphorin 3A Inhibitor Enhance Stroke Recovery via Prostaglandin D2 Synthase",
abstract = "Background and Purpose- Exosomes play a pivotal role in neurogenesis. In the peri-infarct area after stroke, axons begin to regenerate but are inhibited by astrocyte scar formation. The direct effect and underlying molecular mechanisms of astrocyte-derived exosomes on axonal outgrowth after ischemia are not known. Methods- Using a semaphorin 3A (Sema3A) inhibitor, we explored neuronal signaling during axonal outgrowth after ischemia in rats subjected to middle cerebral artery occlusion and in cultured cortical neurons challenged with oxygen-glucose deprivation. Furthermore, we assessed whether this inhibitor suppressed astrocyte activation and regulated astrocyte-derived exosomes to enhance axonal outgrowth after ischemia. Results- In rats subjected to middle cerebral artery occlusion, we administered a Sema3A inhibitor into the peri-infarct area from 7 to 21 days after occlusion. We found that phosphorylated high-molecular weight neurofilament-immunoreactive axons were increased, glial fibrillary acidic protein-immunoreactive astrocytes were decreased, and functional recovery was promoted at 28 days after middle cerebral artery occlusion. In cultured neurons, the Sema3A inhibitor decreased Rho family GTPase 1, increased R-Ras, which phosphorylates Akt and glycogen synthase kinase 3β (GSK-3β), selectively increased phosphorylated GSK-3β in axons, and thereby enhanced phosphorylated high-molecular weight neurofilament-immunoreactive axons after oxygen-glucose deprivation. In cultured astrocytes, the Sema3A inhibitor suppressed activation of astrocytes induced by oxygen-glucose deprivation. Exosomes secreted from ischemic astrocytes treated with the Sema3A inhibitor further promoted axonal elongation and increased prostaglandin D2 synthase expression on microarray analysis. GSK-3β+ and prostaglandin D2 synthase+ neurons were robustly increased after treatment with the Sema3A inhibitor in the peri-infarct area. Conclusions- Neuronal Rho family GTPase 1/R-Ras/Akt/GSK-3β signaling, axonal GSK-3β expression, and astrocyte-derived exosomes with prostaglandin D2 synthase expression contribute to axonal outgrowth and functional recovery after stroke.",
keywords = "astrocytes, axon, exosomes, neurons, semaphorin 3A, stroke",
author = "Kenichiro Hira and Yuji Ueno and Ryota Tanaka and Nobukazu Miyamoto and Kazuo Yamashiro and Toshiki Inaba and Takao Urabe and Hideyuki Okano and Nobutaka Hattori",
year = "2018",
month = "10",
day = "1",
doi = "10.1161/STROKEAHA.118.021272",
language = "English",
volume = "49",
pages = "2483--2494",
journal = "Stroke",
issn = "0039-2499",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Astrocyte-Derived Exosomes Treated With a Semaphorin 3A Inhibitor Enhance Stroke Recovery via Prostaglandin D2 Synthase

AU - Hira, Kenichiro

AU - Ueno, Yuji

AU - Tanaka, Ryota

AU - Miyamoto, Nobukazu

AU - Yamashiro, Kazuo

AU - Inaba, Toshiki

AU - Urabe, Takao

AU - Okano, Hideyuki

AU - Hattori, Nobutaka

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Background and Purpose- Exosomes play a pivotal role in neurogenesis. In the peri-infarct area after stroke, axons begin to regenerate but are inhibited by astrocyte scar formation. The direct effect and underlying molecular mechanisms of astrocyte-derived exosomes on axonal outgrowth after ischemia are not known. Methods- Using a semaphorin 3A (Sema3A) inhibitor, we explored neuronal signaling during axonal outgrowth after ischemia in rats subjected to middle cerebral artery occlusion and in cultured cortical neurons challenged with oxygen-glucose deprivation. Furthermore, we assessed whether this inhibitor suppressed astrocyte activation and regulated astrocyte-derived exosomes to enhance axonal outgrowth after ischemia. Results- In rats subjected to middle cerebral artery occlusion, we administered a Sema3A inhibitor into the peri-infarct area from 7 to 21 days after occlusion. We found that phosphorylated high-molecular weight neurofilament-immunoreactive axons were increased, glial fibrillary acidic protein-immunoreactive astrocytes were decreased, and functional recovery was promoted at 28 days after middle cerebral artery occlusion. In cultured neurons, the Sema3A inhibitor decreased Rho family GTPase 1, increased R-Ras, which phosphorylates Akt and glycogen synthase kinase 3β (GSK-3β), selectively increased phosphorylated GSK-3β in axons, and thereby enhanced phosphorylated high-molecular weight neurofilament-immunoreactive axons after oxygen-glucose deprivation. In cultured astrocytes, the Sema3A inhibitor suppressed activation of astrocytes induced by oxygen-glucose deprivation. Exosomes secreted from ischemic astrocytes treated with the Sema3A inhibitor further promoted axonal elongation and increased prostaglandin D2 synthase expression on microarray analysis. GSK-3β+ and prostaglandin D2 synthase+ neurons were robustly increased after treatment with the Sema3A inhibitor in the peri-infarct area. Conclusions- Neuronal Rho family GTPase 1/R-Ras/Akt/GSK-3β signaling, axonal GSK-3β expression, and astrocyte-derived exosomes with prostaglandin D2 synthase expression contribute to axonal outgrowth and functional recovery after stroke.

AB - Background and Purpose- Exosomes play a pivotal role in neurogenesis. In the peri-infarct area after stroke, axons begin to regenerate but are inhibited by astrocyte scar formation. The direct effect and underlying molecular mechanisms of astrocyte-derived exosomes on axonal outgrowth after ischemia are not known. Methods- Using a semaphorin 3A (Sema3A) inhibitor, we explored neuronal signaling during axonal outgrowth after ischemia in rats subjected to middle cerebral artery occlusion and in cultured cortical neurons challenged with oxygen-glucose deprivation. Furthermore, we assessed whether this inhibitor suppressed astrocyte activation and regulated astrocyte-derived exosomes to enhance axonal outgrowth after ischemia. Results- In rats subjected to middle cerebral artery occlusion, we administered a Sema3A inhibitor into the peri-infarct area from 7 to 21 days after occlusion. We found that phosphorylated high-molecular weight neurofilament-immunoreactive axons were increased, glial fibrillary acidic protein-immunoreactive astrocytes were decreased, and functional recovery was promoted at 28 days after middle cerebral artery occlusion. In cultured neurons, the Sema3A inhibitor decreased Rho family GTPase 1, increased R-Ras, which phosphorylates Akt and glycogen synthase kinase 3β (GSK-3β), selectively increased phosphorylated GSK-3β in axons, and thereby enhanced phosphorylated high-molecular weight neurofilament-immunoreactive axons after oxygen-glucose deprivation. In cultured astrocytes, the Sema3A inhibitor suppressed activation of astrocytes induced by oxygen-glucose deprivation. Exosomes secreted from ischemic astrocytes treated with the Sema3A inhibitor further promoted axonal elongation and increased prostaglandin D2 synthase expression on microarray analysis. GSK-3β+ and prostaglandin D2 synthase+ neurons were robustly increased after treatment with the Sema3A inhibitor in the peri-infarct area. Conclusions- Neuronal Rho family GTPase 1/R-Ras/Akt/GSK-3β signaling, axonal GSK-3β expression, and astrocyte-derived exosomes with prostaglandin D2 synthase expression contribute to axonal outgrowth and functional recovery after stroke.

KW - astrocytes

KW - axon

KW - exosomes

KW - neurons

KW - semaphorin 3A

KW - stroke

UR - http://www.scopus.com/inward/record.url?scp=85055604332&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055604332&partnerID=8YFLogxK

U2 - 10.1161/STROKEAHA.118.021272

DO - 10.1161/STROKEAHA.118.021272

M3 - Article

C2 - 30355116

AN - SCOPUS:85055604332

VL - 49

SP - 2483

EP - 2494

JO - Stroke

JF - Stroke

SN - 0039-2499

IS - 10

ER -