Abstract
Several described growth factors influence the proliferation and regeneration of the intestinal epithelium. Using a transgenic mouse model, we identified a human gene, R-spondin1, with potent and specific proliferative effects on intestinal crypt cells. Human R-spondin1 (hRSpo1) is a thrombospondin domain-containing protein expressed in enteroendocrine cells as well as in epithelial cells in various tissues. Upon injection into mice, the protein induced rapid onset of crypt cell proliferation involving beta-catenin stabilization, possibly by a process that is distinct from the canonical Wnt-mediated signaling pathway. The protein also displayed efficacy in a model of chemotherapy-induced intestinal mucositis and may have therapeutic application in gastrointestinal diseases.
MeSH terms
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Animals
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Antineoplastic Agents / adverse effects
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Cell Line
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Cell Line, Tumor
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Cell Proliferation*
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Chimera
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Colon / cytology
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Colon / pathology
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Cytoskeletal Proteins / metabolism
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Dose-Response Relationship, Drug
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Enteroendocrine Cells / metabolism
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Epithelial Cells / metabolism
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Fibroblast Growth Factor 7
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Fibroblast Growth Factors / pharmacology
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Fluorouracil / adverse effects
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Glucagon-Like Peptides
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Humans
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Intestinal Mucosa / cytology*
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / pathology
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Intestine, Small / cytology
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Intestine, Small / pathology
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Mice
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Mice, Transgenic
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Mitogens*
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Neoplasm Transplantation
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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Peptides / pharmacology
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Proteins / pharmacology
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Recombinant Proteins / pharmacology
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Thrombospondins / genetics
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Thrombospondins / metabolism
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Thrombospondins / pharmacology
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Thrombospondins / physiology*
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Tongue / drug effects
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Tongue / pathology
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Trans-Activators / metabolism
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Wnt Proteins
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Wnt3 Protein
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beta Catenin
Substances
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Antineoplastic Agents
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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FGF7 protein, human
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Fgf7 protein, mouse
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Mitogens
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Peptides
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Proteins
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RSPO1 protein, human
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Recombinant Proteins
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Thrombospondins
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Trans-Activators
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Wnt Proteins
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Wnt3 Protein
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beta Catenin
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Fibroblast Growth Factor 7
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Fibroblast Growth Factors
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Glucagon-Like Peptides
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glucagon-like-immunoreactivity
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Fluorouracil