Sci. Signal., 12 April 2011
Regeneration Recovering from Bladder Injury
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
Understanding how quiescent organs can undergo rapid switching to a proliferative state in response to injury not only should aid in situations where promotion of regeneration is beneficial but also may hold clues to how corruption of this system may lead to cancer. The bladder is one such nearly quiescent organ that can regenerate in response to injury such as that incurred with bladder infections, which are particularly common in women. Shin et al. explored the bladders response to injury by treating mice either with a uropathogenic strain of Escherichia coli or the chemical protamine sulfate and found that the cells of the stromal and epithelial (urothelial) layers underwent rapid proliferation in response to infection, whereas chemical injury triggered proliferation of the urothelial layer only. Sonic hedgehog (Shh) was detected in the basal cells of the urothelial layer. Activity of the Hedgehog pathway occurred in the stromal layer and was detected with a Gli-LacZ reporter (Gli1 is both a mediator of Hedgehog signaling and encoded by a gene that is stimulated by this pathway). Cell labeling experiments with bladders from animals subjected to multiple rounds of infection and recovery indicated that the Shh-expressing basal cells were multipotent and produced all three cell types of the urothelium. Isolated basal cells produced cystlike organoids when cultured for several weeks in Matrigel (a three-dimensional culture system), and single cells from the organoids were capable of generating new organoids. The importance of Hedgehog signaling was demonstrated by the reduction and delay in urothelial and stromal cell proliferation in response to infection in Gli1-deficient bladders. The bladders of Gli1-deficient mice failed to reestablish urothelial integrity within 24 hours after infection, which is lost as the outermost layer of cells exfoliates in response to infection. Although the Gli1-deficient mice had reduced bladder bacterial titers, they exhibited increased bacteria in the kidneys compared with these organs in infected wild-type mice. The authors postulate that the rapid proliferation of urothelial cells may reduce the spread of the bacteria by competing for adhesive interactions that the bacteria would use to migrate from the bladder to the kidney. Hedgehog signaling triggered the induction of genes encoding Wnt2, Wnt4, and Fgf16 (fibroblast growth factor 16) in the stroma, and Gli1-dependent Wnt pathway activity (as assayed by Axin2 expression, which is a target of the Wnt pathway and encodes a component of the Wnt pathway) was detected in the stroma and basal cells of the urothelium. Compromised Wnt signaling, accomplished through pharmacological or genetic manipulations, reduced epithelial and stromal proliferative responses to infection, suggesting that drugs that inhibit Wnt signaling, such as indomethacin, may be contraindicated in patients with bladder infections. These results have implications not only for treatment of bladder infections but also for ex vivo tissue regeneration and cancer.
K. Shin, J. Lee, N. Guo, J. Kim, A. Lim, L. Qu, I. U. Mysorekar, P. A. Beachy, Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature 472, 110–114 (2011). [PubMed]
Citation: N. R. Gough, Recovering from Bladder Injury. Sci. Signal. 4, ec104 (2011).
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