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The Journal of Pathology Oct 2021Stromal-epithelial interactions are critical to the morphogenesis, differentiation, and homeostasis of the prostate, but the molecular identity and anatomy of discrete...
Stromal-epithelial interactions are critical to the morphogenesis, differentiation, and homeostasis of the prostate, but the molecular identity and anatomy of discrete stromal cell types is poorly understood. Using single-cell RNA sequencing, we identified and validated the in situ localization of three smooth muscle subtypes (prostate smooth muscle, pericytes, and vascular smooth muscle) and two novel fibroblast subtypes in human prostate. Peri-epithelial fibroblasts (APOD+) wrap around epithelial structures, whereas interstitial fibroblasts (C7+) are interspersed in extracellular matrix. In contrast, the mouse displayed three fibroblast subtypes with distinct proximal-distal and lobe-specific distribution patterns. Statistical analysis of mouse and human fibroblasts showed transcriptional correlation between mouse prostate (C3+) and urethral (Lgr5+) fibroblasts and the human interstitial fibroblast subtype. Both urethral fibroblasts (Lgr5+) and ductal fibroblasts (Wnt2+) in the mouse contribute to a proximal Wnt/Tgfb signaling niche that is absent in human prostate. Instead, human peri-epithelial fibroblasts express secreted WNT inhibitors SFRPs and DKK1, which could serve as a buffer against stromal WNT ligands by creating a localized signaling niche around individual prostate glands. We also identified proximal-distal fibroblast density differences in human prostate that could amplify stromal signaling around proximal prostate ducts. In human benign prostatic hyperplasia, fibroblast subtypes upregulate critical immunoregulatory pathways and show distinct distributions in stromal and glandular phenotypes. A detailed taxonomy of leukocytes in benign prostatic hyperplasia reveals an influx of myeloid dendritic cells, T cells and B cells, resembling a mucosal inflammatory disorder. A receptor-ligand interaction analysis of all cell types revealed a central role for fibroblasts in growth factor, morphogen, and chemokine signaling to endothelia, epithelia, and leukocytes. These data are foundational to the development of new therapeutic targets in benign prostatic hyperplasia. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Animals; Cellular Microenvironment; Extracellular Matrix; Fibroblasts; Humans; Male; Mice; Prostate; Prostatic Hyperplasia; Single-Cell Analysis
PubMed: 34173975
DOI: 10.1002/path.5751 -
Physiological Reviews Oct 2020The urothelium, which lines the renal pelvis, ureters, urinary bladder, and proximal urethra, forms a high-resistance but adaptable barrier that surveils its... (Review)
Review
The urothelium, which lines the renal pelvis, ureters, urinary bladder, and proximal urethra, forms a high-resistance but adaptable barrier that surveils its mechanochemical environment and communicates changes to underlying tissues including afferent nerve fibers and the smooth muscle. The goal of this review is to summarize new insights into urothelial biology and function that have occurred in the past decade. After familiarizing the reader with key aspects of urothelial histology, we describe new insights into urothelial development and regeneration. This is followed by an extended discussion of urothelial barrier function, including information about the roles of the glycocalyx, ion and water transport, tight junctions, and the cellular and tissue shape changes and other adaptations that accompany expansion and contraction of the lower urinary tract. We also explore evidence that the urothelium can alter the water and solute composition of urine during normal physiology and in response to overdistension. We complete the review by providing an overview of our current knowledge about the urothelial environment, discussing the sensor and transducer functions of the urothelium, exploring the role of circadian rhythms in urothelial gene expression, and describing novel research tools that are likely to further advance our understanding of urothelial biology.
Topics: Animals; Biomechanical Phenomena; Circadian Rhythm; Humans; Urine; Urothelium
PubMed: 32191559
DOI: 10.1152/physrev.00041.2019 -
Pediatric Nephrology (Berlin, Germany) Aug 2022Urothelium is a specialized multilayer epithelium that lines the urinary tract from the proximal urethra to the kidney. In addition to proliferation and differentiation... (Review)
Review
Urothelium is a specialized multilayer epithelium that lines the urinary tract from the proximal urethra to the kidney. In addition to proliferation and differentiation during development, urothelial injury postnatally triggers a robust regenerative capacity to restore the protective barrier between the urine and tissue. Mounting evidence supports the existence of dedicated progenitor cell populations that give rise to urothelium during development and in response to injury. Understanding the cellular and molecular basis for urothelial patterning and repair will inform tissue regeneration therapies designed to ameliorate a number of structural and functional defects of the urinary tract. Here, we review the current understanding of urothelial progenitors and the signaling pathways that govern urothelial development and repair. While most published studies have focused on bladder urothelium, we also discuss literature on upper tract urothelial progenitors. Furthermore, we discuss evidence supporting existence of context-specific progenitors. This knowledge is fundamental to the development of strategies to regenerate or engineer damaged or diseased urothelium.
Topics: Cell Differentiation; Humans; Stem Cells; Urinary Bladder; Urinary Tract; Urothelium
PubMed: 34471946
DOI: 10.1007/s00467-021-05239-w -
Developmental Biology May 2021The prostate develops by epithelial budding and branching processes that occur during fetal and postnatal stages. The adult prostate demonstrates remarkable regenerative... (Review)
Review
The prostate develops by epithelial budding and branching processes that occur during fetal and postnatal stages. The adult prostate demonstrates remarkable regenerative capacity, with the ability to regrow to its original size over multiple cycles of castration and androgen administration. This capacity for controlled regeneration prompted the search for an androgen-independent epithelial progenitor in benign prostatic hyperplasia (BPH) and prostate cancer (PCa). BPH is hypothesized to be a reawakening of ductal branching, resulting in the formation of new proximal glands, all while androgen levels are decreasing in the aging male. Advanced prostate cancer can be slowed with androgen deprivation, but resistance eventually occurs, suggesting the existence of an androgen-independent progenitor. Recent studies indicate that there are multiple castration-insensitive epithelial cell types in the proximal area of the prostate, but not all act as progenitors during prostate development or regeneration. This review highlights how recent cellular and anatomical studies are changing our perspective on the identity of the prostate progenitor.
Topics: Androgen Antagonists; Androgens; Animals; Cell Differentiation; Epithelial Cells; Humans; Male; Organogenesis; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Stem Cells
PubMed: 33529704
DOI: 10.1016/j.ydbio.2020.11.012