Abstract
Wnt signals exercise strong cell-biological and regenerative effects of considerable therapeutic value. There are, however, no specific Wnt agonists and no method for in vivo delivery of purified Wnt proteins. Wnts contain lipid adducts that are required for activity and we exploited this lipophilicity by packaging purified Wnt3a protein into lipid vesicles. Rather than being encapsulated, Wnts are tethered to the liposomal surface, where they enhance and sustain Wnt signaling in vitro. Molecules that effectively antagonize soluble Wnt3a protein but are ineffective against the Wnt3a signal presented by a cell in a paracrine or autocrine manner are also unable to block liposomal Wnt3a activity, suggesting that liposomal packaging mimics the biological state of active Wnts. When delivered subcutaneously, Wnt3a liposomes induce hair follicle neogenesis, demonstrating their robust biological activity in a regenerative context.
Highlights
Wnt signals are implicated in the self-renewal and proliferation of stem cells from a variety of adult tissues [1,2,3] but despite numerous large-scale screenings [4,5,6,7], no specific small molecule Wnt agonists have been identified
Liposomal packaging potentiates the effects of Wnt proteins in vivo
Because of their potential therapeutic value, multiple large scale screens have been conducted in an attempt to identify small molecule agonists of the Wnt pathway [4]
Summary
Wnt signals are implicated in the self-renewal and proliferation of stem cells from a variety of adult tissues [1,2,3] but despite numerous large-scale screenings [4,5,6,7], no specific small molecule Wnt agonists have been identified. Palmitoylation is essential for Wnt activity [1,11]; we reasoned that liposomes might serve as an ideal delivery vehicle for such a hydrophobic molecule. Liposomes are spherical nanovesicles consisting of an aqueous core enclosed in one or more phospholipid layers (reviewed in [12]). Bioengineers and chemical engineers have invested considerable time and effort into manufacturing liposomes that retain the drug or molecule of interest and prevent its degradation. Such preparations would ideally effectively evade detection by the reticuloendothelial system; could be targeted to the tissue of interest; and could be induced to release the drug/molecule when required. The addition of polyethylene glycol (PEG) can prolong the circulatory half-life of liposomes, perhaps acting through steric hindrance ([14,15,16]; reviewed in [17])
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