Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury

Abstract

We have identified cellular and molecular features of the stem cell niche required for marked amplification of mouse colonic epithelial progenitors (ColEPs) that occurs in response to wounding of the epithelium with dextran sodium sulfate. This regenerative response in areas adjacent to breaches in the epithelial barrier depends on the gut microbiota because ColEP proliferation is markedly diminished in germ-free animals. Analysis of conventionally raised C57BL͞6 (B6) knockout mice lacking the Toll-like receptor signal transduction pathway component Myd88 and wild-type animals transplanted with Myd88 ؊/؊ bone marrow, revealed that Myd88-mediated signaling through mesenchymal cells is also required for the ColEP response. Studies of B6 Csf1 op/op (lacking macrophages) mice, Rag1 ؊/؊ mice, and wild-type mice treated with neutrophil-specific Gr1 mAbs, disclosed that macrophages but not lymphocytes or neutrophils are necessary. GeneChip analysis of laser-capture-microdissected mesenchymal cells coupled with immunohistochemical and electron microscopic studies showed that, during the regenerative response, macrophages in the pericryptal stem cell niche express genes associated with their activation and extend processes to directly contact ColEPs near the crypt base. GeneChip analysis also identified a number of potential molecular mediators of regeneration expressed in the pericryptal progenitor niche, including secreted factors that stimulate epithelial proliferation and proteins involved in extracellular matrix and basement membrane function, stability, and growth factor binding. Together, these studies indicate that the colonic epithelial progenitor niche is a dynamic structure in which macrophages function as mobile ''cellular transceivers'' that coordinate inputs from luminal microbes and injured epithelium and transmit regenerative signals to neighboring ColEPs.laser capture microdissection ͉ epithelial-mesenchymal cross-talk ͉ macrophage activation ͉ stem cell ͉ stem cell niche

Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells

“…It has also been shown that a disruption of Tolllike receptor signaling causes an impairment of tissue repair by intestinal epithelial cells (Rakoff-Nahoum et al, 2004). Moreover, activated macrophages are important niche components for intestinal epithelial progenitors in regenerative responses (Pull et al, 2005). Therefore, it is conceivable that downregulation of miR-7 leads to suppression of differentiation, inducing the proliferation of undifferentiated epithelial cells in the inflammatory microenvironment.…”

Carcinogenesis in Mouse Stomach by Simultaneous Activation of the Wnt Signaling and Prostaglandin E2 Pathway

“…Tissue macrophages are implicated in the proliferation of epithelial progenitor cells in the intestine 19 . We thus examined macrophage infiltration in the respective mutant mice by immunostaining.…”

Colony-Stimulating Factor-1 Promotes Kidney Growth and Repair via Alteration of Macrophage Responses

“…3 Embryonic macrophages appear to play a positive trophic role that may have parallel reparative functions in many adult tissues undergoing repair and cellular replacement. 1,20 A number of studies have suggested that infiltrating macrophages along with the trophic factors they release participate in tissue repair of the kidney, 20 -22 brain, 23 skin, 24,25 lung, 26 liver, 27 heart, 28 gastrointestinal tract, 29,30 and skeletal muscle. 31,32 Indeed, the pleiotrophic roles for CSF-1 in reproduction, development of multiple organ systems, and maternal-fetal interactions during pregnancy by macrophage-mediated processes have also been well defined.…”