Summary: Findings could lead to new treatments to help regeneration following trauma.

Source: Kobe University.

A research team led by Associate Professor Mitsuharu Endo and Professor Yasuhiro Minami has pinpointed the mechanism underlying astrocyte-mediated restoration of brain tissue after an injury. This could lead to new treatments that encourage regeneration by limiting damage to neurons incurred by reduced blood supply or trauma. The findings were published on October 11 in the online version of GLIA ahead of print release in January 2017.

When the brain is damaged by trauma or ischemia (restriction in blood supply), immune cells such as macrophages and lymphocytes dispose of the damaged neurons with an inflammatory response. However, an excessive inflammatory response can also harm healthy neurons.

Astrocytes are a type of glial cell, and the most numerous cell within the human cerebral cortex. In addition to their supportive role in providing nutrients to neurons, studies have shown that they have various other functions, including the direct or active regulation of neuronal activities.

It has recently become clear that astrocytes also have an important function in the restoration of injured brain tissue. While astrocytes do not normally proliferate in healthy brains, they start to proliferate and increase their numbers around injured areas and minimize inflammation by surrounding the damaged neurons, other astrocytes, and inflammatory cells that have entered the damaged zone. Until now the mechanism that prompts astrocytes to proliferate in response to injury was unclear.

The research team focused on the fact that the astrocytes which proliferate around injured areas acquire characteristics similar to neural stem cells. The receptor tyrosine kinase Ror2, a cell surface protein, is highly expressed in neural stem cells in the developing brain. Normally the Ror2 gene is “switched off” within adult brains, but these findings showed that when the brain was injured, Ror2 was expressed in a certain population of the astrocytes around the injured area.

Ror2 is an important cell-surface protein that regulates the proliferation of neural stem cells, so the researchers proposed that Ror2 was regulating the proliferation of astrocytes around the injured areas. They tested this using model mice for which the Ror2 gene did not express in astrocytes. In these mice, the number of proliferating astrocytes after injury showed a remarkable decrease, and the density of astrocytes around the injury site was reduced. Using cultured astrocytes, the team analyzed the mechanism for activating the Ror2 gene, and ascertained that basic fibroblast growth factor (bFGF) can “switch on” Ror2 in some astrocytes.

This research showed that in injured brains, the astrocytes that show (high) expression of Ror2 induced by bFGF signal are primarily responsible for starting proliferation. bFGF is produced by different cell types, including neurons and astrocytes in the injury zone that have escaped damage. Among the astrocytes that received these bFGF signals around the injury zone, some express Ror2 and some do not. The fact that proliferating astrocytes after brain injury are reduced during aging raises the possibility that the population of astrocytes that can express Ror2 might decrease during aging, which could cause an increase in senile dementia. Researchers are aiming to clarify the mechanism that creates these different cell populations of astrocytes.

By artificially controlling the proliferation of astrocytes, in the future we can potentially minimize damage caused to neurons by brain injuries and establish a new treatment that encourages regeneration of damaged brain areas.

About this neuroscience disease research article

Funding: Funding provided by Japan Society for the Promotion of Science, Ministry of Education, Culture, Sports, Science and Technology Japan, Takeda Science Foundation.

Source: Eleanor Wyllie – Kobe University

Image Source: NeuroscienceNews.com image is credited to Kobe University.

Original Research: Abstract for “Critical role of Ror2 receptor tyrosine kinase in regulating cell cycle progression of reactive astrocytes following brain injury” by Mitsuharu Endo, Guljahan Ubulkasim, Chiho Kobayashi, Reiko Onishi, Atsu Aiba, and Yasuhiro Minami in Glia. Published online October 11 2016 doi:10.1002/glia.23086

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]Kobe University. “How Brain Tissue Recovers Following an Injury.” NeuroscienceNews. NeuroscienceNews, 16 December 2016.

<https://neurosciencenews.com/tbi-brain-recovery-5764/>.[/cbtab][cbtab title=”APA”]Kobe University. (20116, December 16). How Brain Tissue Recovers Following an Injury. NeuroscienceNews. Retrieved December 16, 2016 from https://neurosciencenews.com/tbi-brain-recovery-5764/[/cbtab][cbtab title=”Chicago”]Kobe University. “How Brain Tissue Recovers Following an Injury.” https://neurosciencenews.com/tbi-brain-recovery-5764/ (accessed December 16, 2016).[/cbtab][/cbtabs]

Abstract

Critical role of Ror2 receptor tyrosine kinase in regulating cell cycle progression of reactive astrocytes following brain injury

Ror2 receptor tyrosine kinase plays crucial roles in developmental morphogenesis and tissue-/organo-genesis. In the developing brain, Ror2 is expressed in neural stem/progenitor cells (NPCs) and involved in the regulation of their stemness. However, it remains largely unknown about its role in the adult brain. In this study, we show that Ror2 is up-regulated in reactive astrocytes in the neocortices within 3 days following stab-wound injury. Intriguingly, Ror2-expressing astrocytes were detected primarily at the area surrounding the injury site, where astrocytes express Nestin, a marker of NPCs, and proliferate in response to injury. Furthermore, we show by using astrocyte-specific Ror2 knockout (KO) mice that a loss of Ror2 in astrocytes attenuates injury-induced proliferation of reactive astrocytes. It was also found that basic fibroblast growth factor (bFGF) is strongly up-regulated at 1 day post injury in the neocortices, and that stimulation of cultured quiescent astrocytes with bFGF restarts their cell cycle and induces expression of Ror2 during the G1 phase predominantly in proliferating cells. By using this culture method, we further show that the proportions of Ror2-expressing astrocytes increase following treatment with the histone deacetylases inhibitors including valproic acid, and that bFGF stimulation increases the levels of Ror2 expression within the respective cells. Moreover, we show that bFGF-induced cell cycle progression into S phase is inhibited or promoted in astrocytes from Ror2 KO mice or NPCs stably expressing Ror2-GFP, respectively. Collectively, these findings indicate that Ror2 plays a critical role in regulating the cell cycle progression of reactive astrocytes following brain injury.

“Critical role of Ror2 receptor tyrosine kinase in regulating cell cycle progression of reactive astrocytes following brain injury” by Mitsuharu Endo, Guljahan Ubulkasim, Chiho Kobayashi, Reiko Onishi, Atsu Aiba, and Yasuhiro Minami in Glia. Published online October 11 2016 doi:10.1002/glia.23086

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