Linking development and regeneration: ephrin-A1 attenuates glial scarring after adulthood stroke
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1
Australian Regenerative Medicine Institute, Monash University,, Bourne Group, Australia
Over the past two decades, 2000+ drugs for the treatment of stroke trialled in rodents have failed in clinical trials. However, persisting evidence demonstrates that neurodevelopmental processes are inexorably linked to neuroregeneration. Therefore, the key to unlocking regenerative capacities after stroke may lie in recapitulating developmental processes through novel pharmaco-therapeutic strategies. Glial scarring and reactive astrogliosis after stroke is a major impediment to neuroregeneration. However, chronic scarring in the infant primate neocortex is markedly less severe compared to adults, allowing greater permissiveness towards regeneration after perinatal stroke. EphA4 is a major modulator of astrogliosis after CNS injuries; however, the ephrin ligands involved in the post-stroke brain remains unknown. A clinically translatable non-human primate (NHP) model of stroke in the infant and adult neocortex was utilised in this project. In infants, ephrin-A1 was upregulated on reactive astrocytes at the ischemic core. Contrastingly, ephrin-A2/ -A5 was upregulated on reactive astrocytes at the ischemic core in adults. In vivo experiments using NHP astrocytes demonstrated that ephrin-A1 induced astrocyte repulsion, suppressed proliferation and pre-vented wound closure. Conversely, ephrin-A2 and -A5 elicited cell attraction, increased proliferation and induced rapid wound closure. Treatment of NHP astrocytes with ephrin-A1 was able to attenuate astrocyte reactivity induced by ephrin-A2/ -A5 activation in vitro. Most importantly, delayed administration of ephrin-A1 after neocortical strokes in rodent and NHP successfully suppressed the reactive astrocyte response after brain injury resulting in a reduction of the density and severity of glial scar, as well as a significant suppression of secondary astrocyte recruitment. We demonstrated that the primate brain undergoes differential Eph/ ephrin mediated astrogliotic responses depending on the age at which stroke occurred. Delayed attenuation of glial scarring through ephrin-A1 treatment results in the generation of an ‘infant-like’ glial scar that may be more permissible towards regeneration and functional recovery after stroke.
Keywords:
Neocortex,
Stroke,
astrocyte,
ephrin,
Astrogliosis
Conference:
14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016.
Presentation Type:
YIC04: Young Investigator Colloquium 4
Topic:
14th Meeting of the Asian-Pacific Society for Neurochemistry
Citation:
Teo
L,
Homman-Ludiye
J and
Bourne
J
(2016). Linking development and regeneration: ephrin-A1 attenuates glial scarring after adulthood stroke.
Conference Abstract:
14th Meeting of the Asian-Pacific Society for Neurochemistry.
doi: 10.3389/conf.fncel.2016.36.00068
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Received:
04 Aug 2016;
Published Online:
11 Aug 2016.
*
Correspondence:
Dr. Leon Teo, Australian Regenerative Medicine Institute, Monash University,, Bourne Group, Melbourne, VIC, Australia, Leon.Teo@monash.edu