Abstract
The regenerative capacity of CNS tracts has ever been a great hurdle to regenerative medicine. Although recent studies have described strategies to stimulate retinal ganglion cells (RGCs) to regenerate axons through the optic nerve, it still remains to be elucidated how these therapies modulate the inhibitory environment of CNS. Thus, the present work investigated the environmental content of the repulsive axon guidance cues, such as Sema3D and its receptors, myelin debris, and astrogliosis, within the regenerating optic nerve of mice submitted to intraocular inflammation + cAMP combined to conditional deletion of PTEN in RGC after optic nerve crush. We show here that treatment was able to promote axonal regeneration through the optic nerve and reach visual targets at twelve weeks after injury. The Regenerating group presented reduced MBP levels, increased microglia/macrophage number, and reduced astrocyte reactivity and CSPG content following optic nerve injury. In addition, Sema3D content and its receptors are reduced in the Regenerating group. Together, our results provide, for the first time, evidence that several regenerative repulsive signals are reduced in regenerating optic nerve fibers following a combined therapy. Therefore, the treatment used made the CNS microenvironment more permissive to regeneration.
Highlights
The regenerative capacity of CNS tracts has ever been a great hurdle to regenerative medicine
The present work investigated the environmental content of the repulsive axon guidance cues, such as Sema3D and its receptors, myelin debris, and astrogliosis, within the regenerating optic nerve of mice submitted to intraocular inflammation + cAMP combined to conditional deletion of PTEN in retinal ganglion cells (RGCs) after optic nerve crush
We investigated the effect of the conditional deletion of PTEN in RGC of mice submitted to intraocular inflammation + cAMP during optic nerve regeneration on the content of the repulsive axon guidance cues Sema3D and its receptors, myelin debris, and astrogliosis, within the axon shaft distal to the lesion site
Summary
The regenerative capacity of CNS tracts has ever been a great hurdle to regenerative medicine. In the last 40 years, CNS regeneration was considered as feasible, with the focus of research on identifying and overcoming the inhibitory nature of CNS to axon growth. During the last 20 years, the research focus has changed to the enhancement of the intrinsic capacity of central neurons to elongate lesioned axons. Approaches that stimulate JAK-STAT and mTOR signaling, such as inflammatory stimuli or genetic deletions of PTEN and/or SOCS3, promoted pronounced regeneration within the optic nerve [9,10,11], Neural Plasticity and when these approaches were combined, there was a partial restoration of the visual function [12]
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