1. Drugging a stem cell compartment using Wnt3a protein as a therapeutic.
- Author
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Dhamdhere GR, Fang MY, Jiang J, Lee K, Cheng D, Olveda RC, Liu B, Mulligan KA, Carlson JC, Ransom RC, Weis WI, and Helms JA
- Subjects
- Animals, Bone Marrow Cells drug effects, Bone Marrow Cells metabolism, Carrier Proteins metabolism, Cell Survival drug effects, Cholic Acids pharmacology, Dose-Response Relationship, Drug, Humans, Hydrophobic and Hydrophilic Interactions, Lipids pharmacology, Liposomes chemistry, Liposomes metabolism, Mice, Protein Binding, Protein Conformation drug effects, Protein Stability, Recombinant Proteins chemistry, Recombinant Proteins pharmacology, Thermodynamics, Wnt Signaling Pathway drug effects, Wnt3A Protein chemistry, Stem Cells drug effects, Stem Cells metabolism, Wnt3A Protein metabolism, Wnt3A Protein pharmacology
- Abstract
The therapeutic potential of Wnt proteins has long been recognized but challenges associated with in vivo stability and delivery have hindered their development as drug candidates. By exploiting the hydrophobic nature of the protein we provide evidence that exogenous Wnt3a can be delivered in vivo if it is associated with a lipid vesicle. Recombinant Wnt3a associates with the external surface of the lipid membrane; this association stabilizes the protein and leads to prolonged activation of the Wnt pathway in primary cells. We demonstrate the consequences of Wnt pathway activation in vivo using a bone marrow engraftment assay. These data provide validation for the development of WNT3A as a therapeutic protein.
- Published
- 2014
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