In vivo replacement of damaged bladder urothelium by Wolffian duct epithelial cells

Joseph, Diya B.; Chandrashekar, Anoop S.; Abler, Lisa L.; Chu, Li‐Fang; Thomson, James A.; Mendelsohn, Cathy; Vezina, Chad M.

doi:10.1073/pnas.1802966115

Cited by 13 publications

(12 citation statements)

References 30 publications

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“…Other fate‐mapping studies demonstrated that superficial cells were derived from proliferation of both basal cells and intermediate cells after injury 3,34‐36 . A more recent study showed that Wolffian duct epithelial cells can also repopulate injured bladders and restore a uroplakin barrier 37 . These conflicting evidence might be the results of heterogeneity and complexity of bladder urothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Single‐cell transcriptomes of mouse bladder urothelium uncover novel cell type markers and urothelial differentiation characteristics

Liu

Gao

et al. 2021

Cell Proliferation

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Objectives Much of the information to date in terms of subtypes and function of bladder urothelial cells were derived from anatomical location or by the expression of a small number of marker genes. To have a comprehensive map of the cellular anatomy of bladder urothelial cells, we performed single‐cell RNA sequencing to thoroughly characterize mouse bladder urothelium. Materials and methods A total of 18,917 single cells from mouse bladder urothelium were analysed by unbiased single‐cell RNA sequencing. The expression of the novel cell marker was confirmed by immunofluorescence using urinary tract infection models. Results Unsupervised clustering analysis identified 8 transcriptionally distinct cell subpopulations from mouse bladder urothelial cells. We discovered a novel type of bladder urothelial cells marked by Plxna4 that may be involved with host response and wound healing. We also found a group of basal‐like cells labelled by ASPM that could be the progenitor cells of adult bladder urothelium. ASPM+ urothelial cells are significantly increased after injury by UPEC. In addition, specific transcription factors were found to be associated with urothelial cell differentiation. At the last, a number of interstitial cystitis/bladder pain syndrome–regulating genes were found differentially expressed among different urothelial cell subpopulations. Conclusions Our study provides a comprehensive characterization of bladder urothelial cells, which is fundamental to understanding the biology of bladder urothelium and associated bladder disease.

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Section: Discussionmentioning

confidence: 99%

Single‐cell transcriptomes of mouse bladder urothelium uncover novel cell type markers and urothelial differentiation characteristics

Liu

Gao

et al. 2021

Cell Proliferation

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“…Under uninjured conditions, the HZ may repress OB-ISC division, as severe HZ injury causes extreme OB-ISC hyperplasia and causes OB-ISCs to cross the midgut/hindgut boundary. Similar cross-tissue injury responses appear to occur in other animals following both injury (Joseph et al 2018) and disease (Badreddine and Wang 2010;Hvid-Jensen et al 2011). Going forward, the midgut/hindgut boundary provides an accessible model to study how tissues respond to injury across organ boundaries, and how disruption of such responses may influence disease progression.…”

Section: Modeling Injury Repair and Cancer Initiation In The Hindgutmentioning

confidence: 83%

Physiology, Development, and Disease Modeling in the Drosophila Excretory System

et al. 2020

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The insect excretory system contains two organ systems acting in concert: the Malpighian tubules and the hindgut perform essential roles in excretion and ionic and osmotic homeostasis. For over 350 years, these two organs have fascinated biologists as a model of organ structure and function. As part of a recent surge in interest, research on the Malpighian tubules and hindgut of Drosophila have uncovered important paradigms of organ physiology and development. Further, many human disease processes can be modeled in these organs. Here, focusing on discoveries in the past 10 years, we provide an overview of the anatomy and physiology of the Drosophila excretory system. We describe the major developmental events that build these organs during embryogenesis, remodel them during metamorphosis, and repair them following injury. Finally, we highlight the use of the Malpighian tubules and hindgut as accessible models of human disease biology. The Malpighian tubule is a particularly excellent model to study rapid fluid transport, neuroendocrine control of renal function, and modeling of numerous human renal conditions such as kidney stones, while the hindgut provides an outstanding model for processes such as the role of cell chirality in development, nonstem cell–based injury repair, cancer-promoting processes, and communication between the intestine and nervous system.

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“…Cre inducible R26R-LacZ or R26R-EYFP alleles were also incorporated to visualize Cremediated recombination. cDnmt1KO newborns do not survive more than a few minutes, are cyanotic and have severely hypoplastic lungs compared to controls (Joseph et al, 2018). DNMT1 protein is expressed throughout the urethral epithelium with the highest expression in prostatic buds.…”

Section: Results: Epithelial Dnmt1 Is Required For Prostatic Bud Formationmentioning

confidence: 99%

“…Prostatic gland genesis is not complete until approximately one month after birth but cDnmt1KO pups die soon after birth (Joseph et al, 2018). We therefore rescued E18.5 prostatic urethras from control and cDnmt1KO embryos and grafted them under the kidney capsule of intact male athymic nude mice for continued growth and development.…”

Section: Dnmt1 Expression Is Required For Prostate Glandular Developmentmentioning

confidence: 99%

“…To circumvent limitations of pharmacological DNMT1 inhibition, we employed targeted genetic approaches to delete Dnmt1 in the urethral epithelium that gives rise to prostatic buds. Targeted genetic approaches have been used previously to interrogate the role of DNMT1 in the developing bladder (Joseph et al, 2018), intestine (Elliott et al, 2015), retina (Nasonkin et al, 2013) and pancreas (Georgia et al, 2013), but the prostate has not been studied in this context. We used a Shhcre driver (Harfe et al, 2004) to conditionally delete Dnmt1 across urethral epithelium from which prostatic buds emerge (cDnmt1KOs) and discovered that DNMT1 is required for prostatic bud formation and elongation and maintains urethral epithelial cell integrity, cell cycle progression and survival.…”

Section: Introductionmentioning

confidence: 99%

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Epithelial DNA methyltransferase-1 regulates cell survival, growth and maturation in developing prostatic buds

Joseph

Chandrashekar

Abler

et al. 2019

Developmental Biology

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DNA methyltransferase 1 (DNMT1) is required for embryogenesis but roles in late forming organ systems including the prostate, which emerges from the urethral epithelium, have not been fully examined. We used a targeted genetic approach involving a Shhcre recombinase to demonstrate requirement of epithelial DNA methyltransferase-1 (Dnmt1) in mouse prostate morphogenesis. Dnmt1 mutant urethral cells exhibit DNA hypomethylation, DNA damage, p53 accumulation and undergo cell cycle arrest and apoptosis. Urethral epithelial cells are disorganized in Dnmt1 mutants, leading to impaired prostate growth and maturation and failed glandular development. We evaluated oriented cell division as a mechanism of bud elongation and widening by demonstrating that mitotic spindle axes typically form parallel or perpendicular to prostatic bud elongation axes. We then deployed a Shh creERT allele to delete Dnmt1 from a subset of urethral epithelial cells, creating mosaic mutants with which to interrogate the requirement for cell division in specific prostatic bud epithelial populations. DNMT1-cell distribution within prostatic buds is not random as would be expected in a process where DNMT1 was not required. Instead, replication competent DNMT1+ cells primarily accumulate in prostatic bud margins and tips while replication impeded DNMT1-cells accumulate in prostatic bud cores. Together, these results highlight the role of DNMT1 in regulating epithelial bud formation by maintaining cell cycle progression and survival of rapidly dividing urethral epithelial cells, which can be extended to the study of other developing epithelial organs. In addition, our results show that prostatic buds consist of two epithelial cell populations with distinct molecular and functional characteristics that could potentially contribute to specialized lineages in the adult prostate.

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In vivo replacement of damaged bladder urothelium by Wolffian duct epithelial cells

Cited by 13 publications

References 30 publications

Single‐cell transcriptomes of mouse bladder urothelium uncover novel cell type markers and urothelial differentiation characteristics

Single‐cell transcriptomes of mouse bladder urothelium uncover novel cell type markers and urothelial differentiation characteristics

Physiology, Development, and Disease Modeling in the Drosophila Excretory System

Epithelial DNA methyltransferase-1 regulates cell survival, growth and maturation in developing prostatic buds

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