R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon
Open accessAbstract
The colonic epithelial turnover is driven by crypt-base stem cells that express the R-spondin receptor Lgr5. Signals that regulate epithelial regeneration upon stem cell injury are largely unknown. Here, we explore the dynamics of Wnt signaling in the colon. We identify two populations of cells with active Wnt signaling: highly proliferative Lgr5+/Axin2+ cells, as well as secretory Lgr5−/Axin2+ cells. Upon Lgr5+ cell depletion, these cells are recruited to contribute to crypt regeneration. Chemical injury induced by DSS leads to a loss of both Lgr5+ cells and Axin2+ cells and epithelial regeneration is driven by Axin2− cells, including differentiated Krt20+ surface enterocytes. Regeneration requires stromal Rspo3, which is present at increased levels upon injury and reprograms Lgr5− but Lgr4+ differentiated cells. In contrast, depletion of stromal Rspo3 impairs crypt regeneration, even upon mild injury. We demonstrate that Rspo3 is essential for epithelial repair via induction of Wnt signaling in differentiated cells.
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The findings provide evidence for a mesenchymal liver niche that controls epithelial cell functions in health and disease, akin to R-spondin-LGR5-mediated mesenchymal-epithelial cross-talk in the gastrointestinal tract.
“Together, our findings provide evidence for a mesenchymal liver niche that controls epithelial cell functions in health and disease, akin to the R-spondin–LGR5-mediated mesenchymal–epithelial cross-talk in the gastrointestinal tract21,22.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [22]
RSPO3 emerged among the top-ten HSC ligands mediating HSC-hepatocyte interactions through its corresponding receptors LGR4 and LGR5.
“RSPO3, a potent positive regulator of the WNT pathway21,22, emerged among the top-ten HSC ligands mediating HSC–hepatocyte interactions through its corresponding receptors LGR4 and LGR5 (Fig. 3b and Supplementary Table 4).”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [22]
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Self-citationPhenotypic heterogeneity and plasticity in colorectal cancer metastasis
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Immune cell-derived signals governing epithelial phenotypes in homeostasis and inflammation
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Excess Dietary Sugar Alters Colonocyte Metabolism and Impairs the Proliferative Response to Damage
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R-spondin family biology and emerging linkages to cancer
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Cell plasticity in regeneration in the stomach and beyond
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Regulation of intestinal epithelial homeostasis by mesenchymal cells
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Scalable, compressed phenotypic screening using pooled perturbations
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Responses of gastric epithelial stem cells and their niche to Helicobacter pylori infection
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Self-citationMetabolic regulation of intestinal homeostasis: molecular and cellular mechanisms and diseases
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Reprogramming cellular identity during intestinal regeneration
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Disruption of stem cell niche–confined R-spondin 3 expression leads to impaired hematopoiesis
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Colon Fibroblasts and Inflammation: Sparring Partners in Colorectal Cancer Initiation?
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Modulation of stem cell fate in intestinal homeostasis, injury and repair
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p53 terminates the regenerative fetal-like state after colitis-associated injury
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Regulation of the regeneration of intestinal stem cells after irradiation
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R-spondin3 is a myokine that differentiates myoblasts to type I fibres
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Rspo3 regulates the abnormal differentiation of small intestinal epithelial cells in diabetic state
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Advanced Progression for the Heterogeneity and Homeostasis of Intestinal Stem Cells
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R-spondin3 promotes the tumor growth of choriocarcinoma JEG-3 cells
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Neuroendocrine control of intestinal regeneration through the vascular niche in Drosophila
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Intestinal Epithelial Axin1 Deficiency Protects Against Colitis via Altered Gut Microbiota
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Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration
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Self-citationMorphogen regulation of stem cell plasticity in intestinal regeneration and carcinogenesis
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Self-citationNeuroendocrine Control of Intestinal Regeneration Through the Vascular Niche in DrosophilaPreprint
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Guiding Principles: Reporting Elements for Gastrointestinal Organoid Research
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Lymphatic endothelia stakeout cryptic stem cells
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Self-citationLithium attenuates graft-versus-host disease via effects on the intestinal stem cell niche
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Microbial-Dependent Recruitment of Immature Myeloid Cells Promotes Intestinal Regeneration
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Lymphatics constitute a novel component of the intestinal stem cell nichePreprint
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Injury-induced intestinal stem cell renewal requires capillary morphogenesis gene 2
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- Authors
- Harnack, C., Berger, H., Antanaviciute, A., Vidal, R., Sauer, S., Simmons, A., Meyer, T. F., & Sigal, M.
- Affiliations
- Max Planck Institute for Infection Biology (DE)
- University of Oxford (GB)
- Max Delbrück Center (DE)
- Corresponding author
- Meyer, Thomas F.
- Sigal, Michael
- ORCID
- Venue
- Nature Communications
- Published
- 2019-09-25
- Volume
- 10
- Issue
- 1
- Pages
- 4368-4368
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6761174
- OpenAlex
- W2975327727
- Cited by
- 137
- References
- 39
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 19 · 2023: 23 · 2022: 25 · 2021: 25 · 2020: 15 · 2019: 1
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (SI 1983 2/1, SI 1983 3/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- RSPO3, Lgr5, Axin2, Wnt signaling, crypt stem cells, DSS-induced colitis, stromal cells, enterocytes, LGR4, epithelial cell turnover, stem cell recovery
- MeSH terms
- Animals, Cell Differentiation, Colitis, Colon, Intestinal Mucosa, Mice, Transgenic, Regeneration, Stem Cells, Mice, Knockout, Thrombospondins, Gene Expression Profiling, Enterocytes, Receptors, G-Protein-Coupled, Keratin-20, Wnt Signaling Pathway, Axin Protein
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