Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury
Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury
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DOI：
10.1073/pnas.0405979102
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发表时间：
2005-01-04
影响因子：
11.1
通讯作者：
Stappenbeck, TS
中科院分区：
文献类型：
--
作者：
Pull, SL;Doherty, JM;Stappenbeck, TS
我们已经确定了细胞和分子特征的干细胞龛所需的显着扩增的小鼠结肠上皮祖细胞（ColEPs），发生在响应损伤的上皮与葡聚糖硫酸钠。在上皮屏障破裂附近区域的这种再生反应取决于肠道微生物群，因为ColEP增殖在无菌动物中显著减少。对缺乏Toll样受体信号转导途径组分Myd 88的常规饲养的C57 BL/6（B6）敲除小鼠和移植Myd 88（-/-）骨髓的野生型动物的分析显示，通过间充质细胞的Myd 88介导的信号传导也是ColEP应答所需的。对B6 Csf 1（op/op）（缺乏巨噬细胞）小鼠、Rag 1（-/-）小鼠和野生型小鼠用嗜中性粒细胞特异性Gr 1 mAb处理的研究表明，巨噬细胞而不是淋巴细胞或中性粒细胞是必需的。激光捕获显微切割的间充质细胞的基因芯片分析加上免疫组织化学和电子显微镜研究表明，在再生反应过程中，巨噬细胞在pericryptal干细胞龛表达基因与他们的激活和扩展过程直接接触ColEPs附近的隐窝基地。基因芯片分析还确定了一些潜在的分子介质的再生中表达的pericryptal祖生态位，包括分泌因子刺激上皮细胞增殖和蛋白质参与细胞外基质和基底膜的功能，稳定性和生长因子结合。总之，这些研究表明，结肠上皮祖细胞生态位是一个动态结构，其中巨噬细胞作为移动的“细胞收发器”，协调来自管腔微生物和受损上皮的输入，并将再生信号传递给邻近的ColEP。
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 C57BL/6 (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.