Abstract
BackgroundWnt proteins modulate development, stem cell fate and cancer through interactions with cell surface receptors. Wnts are cysteine-rich, glycosylated, lipid modified, two domain proteins that are prone to aggregation. The culprit responsible for this behavior is a covalently bound palmitoleoyl moiety in the N-terminal domain.ResultsBy combining murine Wnt3a with phospholipid and apolipoprotein A-I, ternary complexes termed nanodisks (ND) were generated. ND-associated Wnt3a is soluble in the absence of detergent micelles and gel filtration chromatography revealed that Wnt3a co-elutes with ND. In signaling assays, Wnt3a ND induced β-catenin stabilization in mouse fibroblasts as well as hematopoietic stem and progenitor cells (HSPC). Prolonged exposure of HSPC to Wnt3a ND stimulated proliferation and expansion of Lin− Sca-1+ c-Kit+ cells. Surprisingly, ND lacking Wnt3a contributed to Lin− Sca-1+ c-Kit+ cell expansion, an effect that was not mediated through β-catenin.ConclusionsThe data indicate Wnt3a ND constitute a water-soluble transport vehicle capable of promoting ex vivo expansion of HSPC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-016-0218-5) contains supplementary material, which is available to authorized users.
Highlights
Wnt proteins modulate development, stem cell fate and cancer through interactions with cell surface receptors
Wnt3a ND characterization Previous studies have shown that, when ND formation is induced in the presence of hydrophobic bioactive agents or transmembrane proteins, the added components become embedded in the lipid milieu of the product particles [14]
The data presented show that, when reconstituted high-density lipoprotein (rHDL) are formulated in the presence of isolated recombinant murine Wnt3a, it is conferred with aqueous solubility in the absence of detergent micelles and co-elutes with apoA-I following gel filtration chromatography
Summary
Stem cell fate and cancer through interactions with cell surface receptors. Wnts are cysteine-rich, glycosylated, lipid modified, two domain proteins that are prone to aggregation. Members of the Wnt protein family are morphogens that signal cell populations distant from their site of synthesis in a concentration-dependent manner. Murine Wnt3a is fatty acylated with palmitoleic acid on serine 209 [5,6,7]. Replacement of this serine with another amino acid abolishes Wnt lipidation and interferes with intracellular processing and secretion of the protein [5,6,7]
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