Exosomes Mediate Mobilization of Autocrine Wnt10b to Promote Axonal Regeneration in the Injured CNS

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Nardos G. Tassew, Jason Charish, Alireza P. Shabanzadeh, Valbona Luga, Hidekiyo Harada, Nahal Farhani, Philippe D'Onofrio, Brian Choi, Ahmad Ellabban, Philip E.B. Nickerson, Valerie A. Wallace, Paulo D. Koeberle, Jeffrey L. Wrana, Philippe P. Monnier
Developing strategies that promote axonal regeneration within the injured CNS is a major therapeutic challenge, as axonal outgrowth is potently inhibited by myelin and the glial scar. Although regeneration can be achieved using the genetic deletion of PTEN, a negative regulator of the mTOR pathway, this requires inactivation prior to nerve injury, thus precluding therapeutic application. Here, we show that, remarkably, fibroblast-derived exosomes (FD exosomes) enable neurite growth on CNS inhibitory proteins. Moreover, we demonstrate that, upon treatment with FD exosomes, Wnt10b is recruited toward lipid rafts and activates mTOR via GSK3β and TSC2. Application of FD exosomes shortly after optic nerve injury promoted robust axonal regeneration, which was strongly reduced in Wnt10b-deleted animals. This work uncovers an intercellular signaling pathway whereby FD exosomes mobilize an autocrine Wnt10b-mTOR pathway, thereby awakening the intrinsic capacity of neurons for regeneration, an important step toward healing the injured CNS.

Graphical abstract

Teaser

Tassew et al. find that FD exosomes induce relocalization of Wnt10b into lipid rafts, thereby activating mTOR and promoting axonal growth in an inhibitory environment. These exosomes also promote axonal regeneration following optic nerve injury. Thus, they represent a powerful tool to stimulate axonal regrowth in the injured CNS.


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