Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder

• Published in: Nature (London) 2011-04, Vol.472 (7341), p.110-114
• Main Authors: Shin, Kunyoo, Lee, John, Guo, Nini, Kim, James, Lim, Agnes, Qu, Lishu, Mysorekar, Indira U., Beachy, Philip A.
• Format: Article
• Language: English
• Subjects: 631/532/489; 631/80/86; 692/699/255/1318; 692/699/67/589/1336; Animals; Bacterial diseases; Bacterial infections; Biological and medical sciences; Bladder; Cell cycle, cell proliferation; Cell Lineage; Cell physiology; Cell Proliferation; E coli; Epithelial Cells - cytology; Epithelial Cells - metabolism; Feedback, Physiological; Female; Fibroblast Growth Factors - metabolism; Fundamental and applied biological sciences. Psychology; Hedgehog Proteins - metabolism; Humanities and Social Sciences; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; letter; Metazoa; Mice; Molecular and cellular biology; multidisciplinary; Organoids - cytology; Organs; Physiological aspects; Regeneration - physiology; Science; Science (multidisciplinary); Signal Transduction; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Stromal Cells - cytology; Stromal Cells - metabolism; Tumors; Urinary bladder; Urinary Bladder - cytology; Urinary Bladder - drug effects; Urinary Bladder - injuries; Urinary Bladder - metabolism; Urinary Bladder Diseases - chemically induced; Urinary Bladder Diseases - metabolism; Urinary Bladder Diseases - microbiology; Urinary Bladder Diseases - pathology; Uropathogenic Escherichia coli - physiology; Urothelium - cytology; Wnt Proteins - metabolism; Zinc Finger Protein GLI1
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09851

Signalling epidermal growth The maintenance and regeneration of the adult bladder epithelium is poorly understood, yet it is clinically relevant to the development of urinary-tract infections and bladder cancer. A new study provides insight into the cellular and molecular mechanisms underlying the regenerative response to injury within the mammalian urinary bladder. On injury by bacterial infection or chemical agents, a Shh and Wnt signalling feedback circuit between basal cells of the urothelium and the stromal cells that underlie them leads to regenerative proliferation of the bladder epithelia. The maintenance and regeneration of the epithelium of the adult bladder is poorly understood yet it is a clinically relevant process during urinary tract infections and bladder cancer. This study provides insight into the cellular and molecular mechanisms underlying the regenerative response to injury within the mammalian urinary bladder. Upon injury by bacterial infection or chemical agents, a Shh and Wnt signalling feedback circuit between basal cells of the urothelium and the stromal cells that underlie them leads to regenerative proliferation of the bladder epithelia. Epithelial integrity in metazoan organs is maintained through the regulated proliferation and differentiation of organ-specific stem and progenitor cells. Although the epithelia of organs such as the intestine regenerate constantly and thus remain continuously proliferative 1 , other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury 2 , 3 , 4 . The cellular and molecular mechanisms underlying this injury-induced mode of regenerative response are poorly defined. Here we show in mice that the proliferative response to bacterial infection or chemical injury within the bladder is regulated by signal feedback between basal cells of the urothelium and the stromal cells that underlie them. We demonstrate that these basal cells include stem cells capable of regenerating all cell types within the urothelium, and are marked by expression of the secreted protein signal Sonic hedgehog (Shh). On injury, Shh expression in these basal cells increases and elicits increased stromal expression of Wnt protein signals, which in turn stimulate the proliferation of both urothelial and stromal cells. The heightened activity of this signal feedback circuit and the associated increase in cell proliferation appear to be required for