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Stromal <i>Gli2</i> activity coordinates a niche signaling program for mammary epithelial stem cells
Zhao, Chen,Cai, Shang,Shin, Kunyoo,Lim, Agnes,Kalisky, Tomer,Lu, Wan-Jin,Clarke, Michael F.,Beachy, Philip A. American Association for the Advancement of Scienc 2017 Science Vol.356 No.6335
<P>The stem cell niche is a complex local signaling microenvironment that sustains stem cell activity during organ maintenance and regeneration. The mammary gland niche must support its associated stem cells while also responding to systemic hormonal regulation that triggers pubertal changes. We find that Gli2, the major Hedgehog pathway transcriptional effector, acts within mouse mammary stromal cells to direct a hormone-responsive niche signaling program by activating expression of factors that regulate epithelial stem cells as well as receptors for the mammatrophic hormones estrogen and growth hormone. Whereas prior studies implicate stem cell defects in human disease, this work shows that niche dysfunction may also cause disease, with possible relevance for human disorders and in particular the breast growth pathogenesis associated with combined pituitary hormone deficiency.</P>
Control of inflammation by stromal Hedgehog pathway activation restrains colitis
Lee, John J.,Rothenberg, Michael E.,Seeley, E. Scott,Zimdahl, Bryan,Kawano, Sally,Lu, Wan-Jin,Shin, Kunyoo,Sakata-Kato, Tomoyo,Chen, James K.,Diehn, Maximilian,Clarke, Michael F.,Beachy, Philip A. National Academy of Sciences 2016 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.113 No.47
<P>Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+) Foxp3(+) regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.</P>