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 proliferative1, other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury2–4. 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 restoration of urothelial function and, in the case of bacterial injury, may help clear and prevent further spread of infection. Our findings provide a conceptual framework for injury-induced epithelial regeneration in endodermal organs, and may provide a basis for understanding the roles of signalling pathways in cancer growth and metastasis.

Summary Hedgehog (Hh) pathway inhibitors are clinically effective in treatment of basal cell carcinoma and medulloblastoma, but fail therapeutically or even accelerate progression in treatment of endodermally-derived colon and pancreatic cancers. In bladder, another organ of endodermal origin, we find that despite its initial presence in the cancer cell of origin Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression and decreases survival time. This cancer-restraining effect of Hh pathway activity is associated with stromal expression of BMP signals, which stimulate urothelial differentiation. Progression is dramatically reduced by pharmacological activation of BMP pathway activity with low-dose FK506, suggesting an approach to management of human bladder cancer.

Understanding how malignancies arise within normal tissues requires identification of the cancer cell of origin and knowledge of the cellular and tissue dynamics of tumor progression. Here we examine bladder cancer in a chemical carcinogenesis model that mimics muscle-invasive human bladder cancer. With no prior bias regarding genetic pathways or cell types, we prospectively mark or ablate cells to show that muscle-invasive bladder carcinomas arise exclusively from Sonic hedgehog (Shh)-expressing stem cells in basal urothelium. These carcinomas arise clonally from a single cell whose progeny aggressively colonize a major portion of the urothelium to generate a lesion with histological features identical to human carcinoma-in-situ. Shh-expressing basal cells within this precursor lesion become tumor-initiating cells, although Shh expression is lost in subsequent carcinomas. We thus find that invasive carcinoma is initiated from basal urothelial stem cells but that tumor cell phenotype can diverge significantly from that of the cancer cell-of-origin.

Due to a mistake made during manuscript preparation, the Supplemental Data for this article listed incorrect sequences for the primer sets for methylation-specific PCR (MSP). The correct sequences are given below. These corrections do not affect the findings or conclusions of the study.Primer sets used for detection of methylated DNA were 5 0 -ataaagagaaattaggcgc-3 0 and 5 0 -ataaccctcgaaaaacgcg-3 0 (M3), 5 0 -gatgttt gtttaggtcgtagcggtc-3 0 and 5 0 -ccaaactcgaaattcgccgta-3 0 (M2), and 5 0 -tgcgattggttgcgtttcgc-3 0 and 5 0 -cgaaaatacgcataccgcg-3 0 (M1). Primer sets used for detection of unmethylated DNA were 5 0 -ataaagagaaattaggtgt-3 0 and 5 0 -ataaccctcaaaaaacaca-3 0 (M3), 5 0 -tgtttg tttaggttgtagtggttgt-3 0 and 5 0 -cccccaaactcaaaattcaccata-3 0 (M2), and 5 0 -tgtgattggttgtgttttgt-3 0 and 5 0 -caaaaatacacataccaca-3 0 (M1).

Background Mechanically offloading or shielding an incision significantly reduces scarring in both animal and first-in-human studies. Whether or not this strategy would be effective following scar revision surgery was previously unknown. In this article, the authors report that the embrace device, which uses principles of mechanomodulation, significantly improves aesthetic outcomes following scar revision surgery. Methods A prospective, open-label, randomized, single-center study was conducted to evaluate the appearance of scars following revision and embrace treatment. Revision surgery was performed on 12 patients, each acting as his or her own control, and outcomes were assessed at 6 months. A visual analogue scale was used to evaluate each scar, rated by four independent surgeons who were not involved in the study. Results Evaluation of 6-month scar images by four independent surgeons using the visual analogue scale demonstrated a highly significant improvement in scar appearance following embrace treatment (p < 0.005). Conclusion The embrace device represents a powerful new technology for significantly improving scar appearance following revision surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, II.

The authors report the results of a comparative experimental nerve study, using a biologic tissue glue (fibrin) and a synthetic glue (2-cyanoacrylate) in a rat model. A tension-free repair is necessary with the use of fibrin glue, or gapping may occur, thus limiting the use of the agent in promoting re-neurotization. In addition, the human origin of fibrin and thrombin allow for the possibility of viral transmission. The aim of the study was to verify if the synthetic glue is a viable alternative, or whether it causes cellular and tissue lesions. Their main finding was that the cyanoacrylate causes a foreign-body inflammatory reaction and retractile fibrosis, often reducing the nerve diameter up to two-thirds. Cyanoacrylate glue is thus not recommended for peripheral nerve repair.

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 , 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.

The Drosophila Hedgehog receptor functions to regulate the essential downstream pathway component, Smoothened, and to limit the range of signaling by sequestering Hedgehog protein signal within imaginal disc epithelium. Hedgehog receptor function requires both Patched and Ihog activity, the latter interchangeably encoded by interference hedgehog (ihog) or brother of ihog (boi). Here we show that Patched and Ihog activity are mutually required for receptor endocytosis and degradation, triggered by Hedgehog protein binding, and causing reduced levels of Ihog/Boi proteins in a stripe of cells at the anterior/posterior compartment boundary of the wing imaginal disc. This Ihog spatial discontinuity may contribute to classically defined cell segregation and lineage restriction at the anterior/posterior wing disc compartment boundary, as suggested by our observations that Ihog activity mediates aggregation of otherwise non-adherent cultured cells and that loss of Ihog activity disrupts wing disc cell segregation, even with downstream genetic rescue of Hedgehog signal response.