Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection

• Published in: Nature (London) Vol. 501; no. 7465; pp. 107 - 111
• Main Authors: Zhou, Wei-Jie, Geng, Zhen H., Spence, Jason R., Geng, Jian-Guo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.09.2013
• Subjects: 631/136/532/2437; 631/532/2118/2437; 631/80/86; Animals; Cell Lineage; Cell Proliferation - drug effects; Female; Homeostasis - drug effects; Humanities and Social Sciences; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Intestines - cytology; Intestines - drug effects; Intestines - pathology; Intestines - radiation effects; letter; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - radiotherapy; Neoplasms - drug therapy; Neoplasms - pathology; Neoplasms - radiotherapy; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - pharmacology; Receptors, Immunologic - deficiency; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Regeneration - drug effects; Regeneration - radiation effects; Roundabout Proteins; Science; Signal Transduction - drug effects; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - radiation effects; Survival Rate; Thrombospondins - administration & dosage; Thrombospondins - metabolism; Thrombospondins - pharmacology; Wnt Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12416

Evidence of crosstalk between the Robo/Slit and Wnt signalling pathways is provided, and R-spondin signalling is shown to enhance canonical Wnt signalling and increase the proliferation of intestinal stem cells. Robo/Slit and Wnt signal tissue repair Jian-Guo Geng and colleagues have identified previously unrecognized crosstalk between the Robo–Slit and the Wnt signalling pathways. The authors studied how the Slit2 ligand and its receptor Robo1 influence intestinal crypt morphology and epithelial homeostasis. Reduction of Robo1 levels causes dramatic shortening of intestinal villi in the mouse intestine as well as a lower density of crypts, the niche occupied by intestinal stem cells. The authors provide evidence that Robo1 is a receptor for R-spondin 1, a secreted protein with known synergy for Wnt signalling. Combined with Slit2, R-spondin 1 signalling enhances canonical Wnt signalling and elevates the proliferation and lineage dynamics of intestinal stem cells. These findings indicate that Slit2 and R-spondin 1 cooperatively induce intestinal stem cells for intestinal homeostasis and repair, and significantly prolong overall survival following lethal doses of chemoradiotherapy. Cancer research has been rightly and successfully focused on prevention, early detection, and identification of specific molecular targets that distinguish the malignant cells from the neighbouring benign cells 1 . However, reducing lethal tissue injury caused by intensive chemoradiotherapy during treatment of late-stage metastatic cancers remains a key clinical challenge. Here we tested whether the induction of adult stem cells could repair chemoradiation-induced tissue injury and prolong overall survival in mice. We found that intestinal stem cells (ISCs) 2 expressed Slit2 and its single-span transmembrane cell-surface receptor roundabout 1 (Robo1) 3 , 4 . Partial genetic deletion of Robo1 decreased ISC numbers and caused villus hypotrophy, whereas a Slit2 transgene increased ISC numbers and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin 1 (Rspo1; a Wnt agonist) 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 plus Slit2 reduced ISC loss, mitigated gut impairment and protected animals from death, without concomitantly decreasing tumour sensitivity to chemotherapy. Therefore Rspo1 and Slit2 may act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.