Tissue-targeted R-spondin mimetics for liver regeneration
Open accessAbstract
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.
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Treatment with RSPO ligands or tetravalent FZD-LRP antibodies enhanced WNT/β-catenin signalling, accelerated liver regeneration and increased metabolic function in diverse injury models.
“Treatment with RSPO ligands44,158 or tetravalent FZD-LRP antibodies25 enhanced WNT/β-catenin signalling, accelerated liver regeneration and increased metabolic function in diverse injury models.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [158]
The Results section (“Liver-targeted RSPO mimetics improves liver function in diseased mouse models”; page unavailable) reports increased Wnt-target gene expression, a proliferation marker, and faster recovery of a liver-function measure after RSPO treatment. It also reports increased expression of metabolic enzymes, but only suggests a potential metabolic benefit. The experiments use a chronic thioacetamide injury model, not diverse injury models, and do not directly demonstrate accelerated liver regeneration. (LLM, conf=0.85)
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- Authors
- Zhang, Z., Broderick, C., Nishimoto, M., Yamaguchi, T., Lee, S.-J., Zhang, H., Chen, H., Patel, M., Ye, J., Ponce, A., Brady, J., Baribault, H., Li, Y., & Yeh, W.-C.
- Affiliations
- Surrozen, Inc. (United States) (US)
- Corresponding author
- Li, Yang
- Yeh, Wen-Chen
- ORCID
- Venue
- Scientific Reports
- Published
- 2020-08-18
- Volume
- 10
- Issue
- 1
- Pages
- 13951-13951
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7435267
- OpenAlex
- W3065573086
- Cited by
- 50
- References
- 29
- Citations by year
- 2025: 8 · 2024: 16 · 2023: 14 · 2022: 9 · 2021: 3
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Surrozen, Inc.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- R-spondin, RSPO2, Wnt signaling, liver regeneration, ASGR1, liver function, cell proliferation
- MeSH terms
- R-Spondins, Animals, Cell Line, Humans, Liver Regeneration, Male, Mice, Inbred C57BL, Signal Transduction, Thrombospondins, Intercellular Signaling Peptides and Proteins, Asialoglycoprotein Receptor, Receptors, G-Protein-Coupled, Ubiquitin-Protein Ligases, Cell Proliferation, beta Catenin, Mice, Drug Discovery, HEK293 Cells, Wnt Signaling Pathway
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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