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 BASIC RESEARCH: Inducing intestinal growth The small-intestinal epithelium is composed of proliferative-crypt and differentiating-villus compartments. Pluripotent stem cells (believed to reside near crypt bases) give rise to progenitors that proliferate and migrate either toward the villus while differentiating into enterocyte, goblet, and enteroendocrine cells or toward the crypt bases while differentiating into Paneth cells. The signaling pathway mediated by the Wnt– The discovery by Kim and colleagues1 that R-spondin1, a newly identified human protein, activates Kim et al.1 discovered the effects of R-spondin1 during in vivo screening of secreted proteins. They engineered transgenic "knock-in" mice by inducing their B lymphocytes to express a specific human gene predicted to encode a secreted protein. They then screened the mice, each of which expressed a different protein, for particular phenotypes. The R-spondin1 knock-in mice had dramatically enlarged small intestines that were more than twice as heavy as the intestines of wild-type mice and caused noticeable distention of the abdomen. Both the diameter and the length of the small intestine were affected. Histochemical analysis revealed an expansion of the proliferative zones of the small and large intestines, but the numbers of differentiated goblet and Paneth cells were similar to those in wild-type mice. Cells in the proliferative zone showed intense staining of cytoplasmic These findings are consistent with the previous observation that R-spondin2 activates the Normally, cytoplasmic On binding to a receptor complex on the cell surface, Wnt protein initiates signaling pathways that disrupt the degradation of This, in turn, results in an increase in Activated R-spondin1 may exert some of its effects independently of Wnt signaling, because Kim et al. found that treatment of a human-embryonic-kidney cell line with a potent Wnt inhibitor only partially inhibited R-spondin1–mediated activation of
Mice were injected with carcinoma cells five days before intravenous treatment was initiated with fluorouracil (days 1 through 5) and either saline (Panel A, days 1 through 8), or R-spondin1 (Panel B, 50 µg per day intravenously on days 1 through 8) to assess the effects on chemotherapy-induced adverse effects and tumor size.1 In fluorouracil-treated mice, those that received R-spondin1 (Panel B) had a reduction in fluorouracil-mediated adverse effects (enteritis, diarrhea, and weight loss), whereas no such effects were observed in mice given saline (Panel A). In Panel A, pluripotent stem cells believed to reside near crypt bases give rise to progenitors that proliferate by means of Wnt signaling and the activation of Mutations in the APC gene can result in excessive activation of On the other hand, activation of Kim et al. observed that treatment with R-spondin1 mitigated the adverse gastrointestinal effects (enteritis, diarrhea, weight loss, and impaired epithelial integrity) associated with the chemotherapeutic agent fluorouracil without increasing tumor growth, as compared with fluorouracil treatment alone (Figure 1). 1 A single dose of R-spondin1 resulted in rapid proliferation of crypt progenitors, with normalization of the levels by 48 hours — demonstrating the potential short-term beneficial effects of this protein on chemotherapy-induced injuries. Other intestinal diseases (such as inflammatory bowel disease, radiation-induced enteritis, and intestinal ischemia) involving acute and chronic epithelial injury and impaired epithelial healing may prove to be responsive to R-spondin1. The effects of various members of the family of growth factors, such as fibroblast growth factors and glucagon-like peptide 2 (GLP-2), on epithelial growth and healing are being evaluated for their therapeutic benefit. Kim et al.1 observed that R-spondin1 induced a more dramatic expansion of the proliferative zone than did fibroblast growth factor 7 or GLP-2, perhaps reflecting direct activation of Epithelial proliferative effects may be mediated directly or indirectly — for example, through vascular endothelial cells and enteric neurons. The sustained effects on intestinal growth observed in R-spondin1–chimeric mice also suggest that this protein may have therapeutic benefits in the short-gut syndrome. However, how R-spondin1 affects the balance between intestinal epithelial healing and excessive growth and neoplasia, as well as its effects on other organs, will need to be evaluated carefully as it is considered for various therapeutic purposes. Questions remain regarding the role and regulation of R-spondin1. What regulates its expression? With which receptors or receptor complexes does it interact? Does it initiate signaling pathways other than the Studies of knockout models would help define the degree to which this newly identified protein is essential for the maintenance of epithelial integrity. The elucidation of the full spectrum of the biologic effects of R-spondin1 will enable us to understand its physiological role as well as guide potential new therapeutic approaches.
Next Inducing Intestinal Growth From the Department of Medicine, University of Chicago, Chicago. References
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-catenin cascade has a central role in determining the balance of these different types of cells — in other words, it has an important influence on the cell's tendency to differentiate or proliferate. 
