The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).

Defense against attaching and effacing (A/E) bacteria requires the sequential generation of interleukin 23 (IL-23) and IL-22 to induce protective mucosal responses. While CD4+ and NKp46+ innate lymphoid cells (ILCs) are the critical source of IL-22 during infection, the precise source of IL-23 is unclear. We used genetic techniques to deplete specific subsets of classical dendritic cells (cDCs) and analyzed immunity to the A/E pathogen Citrobacter rodentium. We found that Notch2 controlled the terminal stage of cDC differentiation. Notch2-dependent intestinal CD11b+ cDCs, but not Batf3-dependent CD103+ cDCs, were an obligate source of IL-23 required to survive C. rodentium infection. These results provide the first demonstration of a non-redundant function of CD11b+ cDCs in response to pathogens in vivo.

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IL-6 is a pleiotropic cytokine often associated with inflammation. Inhibition of this pathway has led to successful treatment of rheumatoid arthritis, but one unforeseen potential complication of anti-IL-6 therapy is bowel perforation. Within the intestine, IL-6 has been shown to prevent epithelial apoptosis during prolonged inflammation. The role of IL-6 in the intestine during an initial inflammatory insult is unknown. Here, we evaluate the role of IL-6 at the onset of an inflammatory injury. Using two murine models of bowel injury – wound by biopsy and bacterial triggered colitis – we demonstrated that IL-6 is induced soon after injury by multiple cell types including intraepithelial lymphocytes. Inhibition of IL-6 resulted in impaired wound healing due to decreased epithelial proliferation. Using intestinal tissue obtained from patients who underwent surgical resection of the colon due to traumatic perforation, we observed cells with detectable IL-6 within the area of perforation and not at distant sites. Our data demonstrate the important role of IL-6 produced in part by intraepithelial lymphocytes at the onset of an inflammatory injury for epithelial proliferation and wound repair.

Background & Aims Prostaglandin-endoperoxide synthase (Ptgs)2 is an enzyme involved in prostaglandin production during the response to mucosal damage. Its expression is regulated, in part, by mRNA-binding proteins that control the stability of Ptgs2 mRNA. We used a precise system of colonic injury and repair to identify Ptgs2 mRNA-binding proteins. Methods We used endoscopy-guided mucosal excision to create focal injury sites in colons of mice. Wound beds from wild-type, Ptgs2−/−, Ptgs2+/−, and Myd88−/− mice were analyzed at 2-day intervals following injury for aspects of repair and Ptgs2 expression. We used cultured colonic mesenchymal stem cells (cMSCs) that express Ptgs2 to identify and analyze molecules that regulate Ptgs2 expression. Results Ptgs2−/− mice had defects in wound repair, validating the biopsy technique as a system to study the regulation of Ptgs2. Ptgs2+/− mice had similar defects in wound healing, so full induction of Ptgs2 is required for wound repair. In wild-type mice, levels of Ptgs2 mRNA increased significantly in the wound bed 2 and 4 days after injury; the highest levels of Ptgs2 were observed in cMSCs. In a functional small hairpin RNA knockdown screen, we identified Igf2bp1, a VICKZ mRNA-binding protein, as a regulator of Ptgs2 expression in cMSCs. Igf2bp1 also interacted physically with Ptgs2 mRNA. Igf2bp1 expression was induced exclusively in wound-bed cMSCs, and full induction of Ptgs2 and Igf2bp1 during repair required Myd88. Conclusions We identified Igf2bp1 as a regulator of Ptgs2 mRNA in mice. Igf2bp1 is required for full induction of Ptgs2 mRNA in cMSCs.