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Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacement.

Liang FX, Bosland MC, Huang H, Romih R, Baptiste S, Deng FM, Wu XR, Shapiro E, Sun TT - J. Cell Biol. (2005)

Bottom Line: Although the epithelial lining of much of the mammalian urinary tract is known simply as the urothelium, this epithelium can be divided into at least three lineages of renal pelvis/ureter, bladder/trigone, and proximal urethra based on their embryonic origin, uroplakin content, keratin expression pattern, in vitro growth potential, and propensity to keratinize during vitamin A deficiency.During vitamin A deficiency, mouse urothelium form multiple keratinized foci in proximal urethra probably originating from scattered K14-positive basal cells, and the keratinized epithelium expands horizontally to replace the surrounding normal urothelium.These data suggest that the urothelium consists of multiple cell lineages, that trigone urothelium is closely related to the urothelium covering the rest of the bladder, and that lineage heterogeneity coupled with cell migration/replacement form the cellular basis for urothelial squamous metaplasia.

View Article: PubMed Central - PubMed

Affiliation: Epithelial Biology Unit, The Ronald O. Perelman Department of Dermatology.

ABSTRACT
Although the epithelial lining of much of the mammalian urinary tract is known simply as the urothelium, this epithelium can be divided into at least three lineages of renal pelvis/ureter, bladder/trigone, and proximal urethra based on their embryonic origin, uroplakin content, keratin expression pattern, in vitro growth potential, and propensity to keratinize during vitamin A deficiency. Moreover, these cells remain phenotypically distinct even after they have been serially passaged under identical culture conditions, thus ruling out local mesenchymal influence as the sole cause of their in vivo differences. During vitamin A deficiency, mouse urothelium form multiple keratinized foci in proximal urethra probably originating from scattered K14-positive basal cells, and the keratinized epithelium expands horizontally to replace the surrounding normal urothelium. These data suggest that the urothelium consists of multiple cell lineages, that trigone urothelium is closely related to the urothelium covering the rest of the bladder, and that lineage heterogeneity coupled with cell migration/replacement form the cellular basis for urothelial squamous metaplasia.

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Focal urothelial keratinization in the proximal urethra and the maintenance of a sharp boundary between the advancing keratinized epithelium and the retreating normal urothelium. The urinary tract of vitamin A–deficient mice (28-wk-old female; see Materials and methods) was dissected, and adjacent sections were stained with either a monoclonal antibody to keratin K10 (a, c, e, and g) or with the AU1 antibody to UP IIIa (b, d, f, and h). Sections shown in a and b are from the trigone, whereas those in g and h are from the bladder wall; sections shown in c–f are from intermediate zones. Note the complete keratinization of the trigone urothelium (K10 positive and UP negative) and the largely normal urothelium (K10 negative and UP positive) of the bladder wall. (i–l) Hematoxylin- and eosin-stained sections showing the sharp boundary (arrows) between the keratinized epithelium (asterisks) and the normal-appearing urothelium. (m) Depicts schematically the expansion of the K10-positive epithelium, which originates from the proximal urethra and the trigone area and expands to the rest of the bladder except the top dome. B, bladder; K, kidney; L, lumen; UR, ureter; PU, proximal urethra; TG, trigone. Bars (a–h), 400 μm; (j) 100 μm; (i, k, and l) 200 μm.
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fig3: Focal urothelial keratinization in the proximal urethra and the maintenance of a sharp boundary between the advancing keratinized epithelium and the retreating normal urothelium. The urinary tract of vitamin A–deficient mice (28-wk-old female; see Materials and methods) was dissected, and adjacent sections were stained with either a monoclonal antibody to keratin K10 (a, c, e, and g) or with the AU1 antibody to UP IIIa (b, d, f, and h). Sections shown in a and b are from the trigone, whereas those in g and h are from the bladder wall; sections shown in c–f are from intermediate zones. Note the complete keratinization of the trigone urothelium (K10 positive and UP negative) and the largely normal urothelium (K10 negative and UP positive) of the bladder wall. (i–l) Hematoxylin- and eosin-stained sections showing the sharp boundary (arrows) between the keratinized epithelium (asterisks) and the normal-appearing urothelium. (m) Depicts schematically the expansion of the K10-positive epithelium, which originates from the proximal urethra and the trigone area and expands to the rest of the bladder except the top dome. B, bladder; K, kidney; L, lumen; UR, ureter; PU, proximal urethra; TG, trigone. Bars (a–h), 400 μm; (j) 100 μm; (i, k, and l) 200 μm.

Mentions: To analyze the metaplastic responses of various urothelial compartments, we fed mice with a vitamin A–deficient diet (see Materials and methods). Mouse bladders and associated structures were serial sectioned to visualize proximal urethra, trigone, bladder wall, and bladder dome, and sections were stained with antibodies to keratin K10 (marker for keratinization; Fig. 3, a, c, e, and g) and to UPs (Fig. 3, b, d, f, and h). The K10 and UP staining, as seen in adjacent sections, were found to be mutually exclusive. Keratinization of the urothelia occurred much earlier (∼8 wk of age) in female than in male mice (∼48 wk). Studies of female mice that had been on vitamin A–deficient diets for various lengths of time (8–56 wk) showed that keratinizing squamous metaplasia occurred initially in the proximal urethra and trigone (Fig. 3, a–d) and expanded upwards (Fig. 3, e–h), although the very top of the dome was rarely involved (Table II; schematically summarized in Fig. 3 m). The K10- and UP-positive epithelia were morphologically indistinguishable from the epidermis and normal urothelium, respectively, and these two epithelia always maintained a sharp boundary (Fig. 3, i–l), with no intermediate cells expressing both K10 and UP markers (Fig. 3, a–h).


Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacement.

Liang FX, Bosland MC, Huang H, Romih R, Baptiste S, Deng FM, Wu XR, Shapiro E, Sun TT - J. Cell Biol. (2005)

Focal urothelial keratinization in the proximal urethra and the maintenance of a sharp boundary between the advancing keratinized epithelium and the retreating normal urothelium. The urinary tract of vitamin A–deficient mice (28-wk-old female; see Materials and methods) was dissected, and adjacent sections were stained with either a monoclonal antibody to keratin K10 (a, c, e, and g) or with the AU1 antibody to UP IIIa (b, d, f, and h). Sections shown in a and b are from the trigone, whereas those in g and h are from the bladder wall; sections shown in c–f are from intermediate zones. Note the complete keratinization of the trigone urothelium (K10 positive and UP negative) and the largely normal urothelium (K10 negative and UP positive) of the bladder wall. (i–l) Hematoxylin- and eosin-stained sections showing the sharp boundary (arrows) between the keratinized epithelium (asterisks) and the normal-appearing urothelium. (m) Depicts schematically the expansion of the K10-positive epithelium, which originates from the proximal urethra and the trigone area and expands to the rest of the bladder except the top dome. B, bladder; K, kidney; L, lumen; UR, ureter; PU, proximal urethra; TG, trigone. Bars (a–h), 400 μm; (j) 100 μm; (i, k, and l) 200 μm.
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fig3: Focal urothelial keratinization in the proximal urethra and the maintenance of a sharp boundary between the advancing keratinized epithelium and the retreating normal urothelium. The urinary tract of vitamin A–deficient mice (28-wk-old female; see Materials and methods) was dissected, and adjacent sections were stained with either a monoclonal antibody to keratin K10 (a, c, e, and g) or with the AU1 antibody to UP IIIa (b, d, f, and h). Sections shown in a and b are from the trigone, whereas those in g and h are from the bladder wall; sections shown in c–f are from intermediate zones. Note the complete keratinization of the trigone urothelium (K10 positive and UP negative) and the largely normal urothelium (K10 negative and UP positive) of the bladder wall. (i–l) Hematoxylin- and eosin-stained sections showing the sharp boundary (arrows) between the keratinized epithelium (asterisks) and the normal-appearing urothelium. (m) Depicts schematically the expansion of the K10-positive epithelium, which originates from the proximal urethra and the trigone area and expands to the rest of the bladder except the top dome. B, bladder; K, kidney; L, lumen; UR, ureter; PU, proximal urethra; TG, trigone. Bars (a–h), 400 μm; (j) 100 μm; (i, k, and l) 200 μm.
Mentions: To analyze the metaplastic responses of various urothelial compartments, we fed mice with a vitamin A–deficient diet (see Materials and methods). Mouse bladders and associated structures were serial sectioned to visualize proximal urethra, trigone, bladder wall, and bladder dome, and sections were stained with antibodies to keratin K10 (marker for keratinization; Fig. 3, a, c, e, and g) and to UPs (Fig. 3, b, d, f, and h). The K10 and UP staining, as seen in adjacent sections, were found to be mutually exclusive. Keratinization of the urothelia occurred much earlier (∼8 wk of age) in female than in male mice (∼48 wk). Studies of female mice that had been on vitamin A–deficient diets for various lengths of time (8–56 wk) showed that keratinizing squamous metaplasia occurred initially in the proximal urethra and trigone (Fig. 3, a–d) and expanded upwards (Fig. 3, e–h), although the very top of the dome was rarely involved (Table II; schematically summarized in Fig. 3 m). The K10- and UP-positive epithelia were morphologically indistinguishable from the epidermis and normal urothelium, respectively, and these two epithelia always maintained a sharp boundary (Fig. 3, i–l), with no intermediate cells expressing both K10 and UP markers (Fig. 3, a–h).

Bottom Line: Although the epithelial lining of much of the mammalian urinary tract is known simply as the urothelium, this epithelium can be divided into at least three lineages of renal pelvis/ureter, bladder/trigone, and proximal urethra based on their embryonic origin, uroplakin content, keratin expression pattern, in vitro growth potential, and propensity to keratinize during vitamin A deficiency.During vitamin A deficiency, mouse urothelium form multiple keratinized foci in proximal urethra probably originating from scattered K14-positive basal cells, and the keratinized epithelium expands horizontally to replace the surrounding normal urothelium.These data suggest that the urothelium consists of multiple cell lineages, that trigone urothelium is closely related to the urothelium covering the rest of the bladder, and that lineage heterogeneity coupled with cell migration/replacement form the cellular basis for urothelial squamous metaplasia.

View Article: PubMed Central - PubMed

Affiliation: Epithelial Biology Unit, The Ronald O. Perelman Department of Dermatology.

ABSTRACT
Although the epithelial lining of much of the mammalian urinary tract is known simply as the urothelium, this epithelium can be divided into at least three lineages of renal pelvis/ureter, bladder/trigone, and proximal urethra based on their embryonic origin, uroplakin content, keratin expression pattern, in vitro growth potential, and propensity to keratinize during vitamin A deficiency. Moreover, these cells remain phenotypically distinct even after they have been serially passaged under identical culture conditions, thus ruling out local mesenchymal influence as the sole cause of their in vivo differences. During vitamin A deficiency, mouse urothelium form multiple keratinized foci in proximal urethra probably originating from scattered K14-positive basal cells, and the keratinized epithelium expands horizontally to replace the surrounding normal urothelium. These data suggest that the urothelium consists of multiple cell lineages, that trigone urothelium is closely related to the urothelium covering the rest of the bladder, and that lineage heterogeneity coupled with cell migration/replacement form the cellular basis for urothelial squamous metaplasia.

Show MeSH
Related in: MedlinePlus