Tissue-targeted R-spondin mimetics for liver regeneration

• Published in: Scientific reports Vol. 10; no. 1; p. 13951
• Main Authors: Zhang, Zhengjian, Broderick, Caroline, Nishimoto, Marni, Yamaguchi, Teppei, Lee, Sung-Jin, Zhang, Haili, Chen, Hui, Patel, Mehaben, Ye, Jay, Ponce, Alberto, Brady, Jennifer, Baribault, Hélène, Li, Yang, Yeh, Wen-Chen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.08.2020; Nature Publishing Group
• Subjects: 631/154; 631/92; Animals; Asialoglycoprotein Receptor - drug effects; Asialoglycoprotein Receptor - metabolism; beta Catenin - metabolism; Cell Line; Cell Proliferation; Drug Discovery - methods; HEK293 Cells; Hepatocytes; Humanities and Social Sciences; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Intestine; Liver; Liver diseases; Liver Regeneration - drug effects; Liver Regeneration - physiology; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Receptors, G-Protein-Coupled - metabolism; Science; Science (multidisciplinary); Signal Transduction - drug effects; Thrombospondins - metabolism; Thrombospondins - therapeutic use; Tissues; Ubiquitin-Protein Ligases - metabolism; Wnt protein; Wnt Signaling Pathway - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-70912-3

R-spondin (RSPO) proteins amplify Wnt signaling and stimulate regeneration in a variety of tissues. To repair tissue in a tissue-specific manner, tissue-targeted RSPO mimetic molecules are desired. Here, we mutated RSPO (RSPO2 F105R/F109A) to eliminate LGR binding while preserving ZNRF3/RNF43 binding and targeted the mutated RSPO to a liver specific receptor, ASGR1. The resulting bi-specific molecule (αASGR1-RSPO2-RA) enhanced Wnt signaling effectively in vitro, and its activity was limited to ASGR1 expressing cells. Systemic administration of αASGR1-RSPO2-RA in mice specifically upregulated Wnt target genes and stimulated cell proliferation in liver but not intestine (which is more responsive to non-targeted RSPO2) in healthy mice, and improved liver function in diseased mice. These results not only suggest that a tissue-specific RSPO mimetic protein can stimulate regeneration in a cell-specific manner, but also provide a blueprint of how a tissue-specific molecule might be constructed for applications in a broader context.