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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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Models of epithelial metaplasia. (A) A terminally differentiated cell (DC; square) can, in response to environmental changes (gray), directly transform into a different type of terminally differentiated cell (diamond; the transdifferentiation model). (B) The terminally differentiated cells can convert back to a relatively undifferentiated (or stem) cell, which can then, in response to environmental and/or mesenchymal changes (beige), differentiate along a different pathway, yielding a distinct phenotype (the dedifferentiation and redifferentiation model). (C) Under normal conditions, the pluripotent stem cells give rise to terminal differentiated cells of a particular phenotype; environmental changes may induce such stem cells to undergo an alternative pathway of differentiation. The recently demonstrated plasticity of certain stem cells, in response to strong mesenchymal niche influence, may fit this model (pluripotent or plastic stem cell model). (D) The tissue contains two separate populations of stem cells: one of them normally gives rise to the (dominant population of) terminally differentiated cell types, whereas the other lays dormant. Environmental changes, including the alteration of the stem cell niche, suppress the growth and differentiation of the originally dominant stem cell (yellow) while activating the originally dormant stem cell (red) that now gives rise to an entirely different phenotype (the selective expansion model). The activation of the esophageal gland stem cell in Barrett's esophagus (Gillen et al., 1988; Kumagai et al., 2003), the vitamin A deficiency–induced squamous metaplasia of tracheal epithelium (Wolbach and Howe, 1925; Nasiell, 1963), uterine epithelium (Ponnamperuma et al., 1999), and cervical epithelium (Darwiche et al., 1993) may fall into this category. (E) The tissue contains two separate cell lineages that occupy different domains separated with well-defined boundaries. Environmental changes such as vitamin A deficiency favor the expansion of one cell lineage over another, thus allowing one cell type to expand and invade into another cell lineage's domain (the cell lineage heterogeneity and replacement model). This last model can best explain our data on urothelial keratinizing squamous metaplasia that is induced by vitamin A deficiency. (C–E) The parallel red bars denote that the process/pathway is blocked. SC, stem cell.
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fig6: Models of epithelial metaplasia. (A) A terminally differentiated cell (DC; square) can, in response to environmental changes (gray), directly transform into a different type of terminally differentiated cell (diamond; the transdifferentiation model). (B) The terminally differentiated cells can convert back to a relatively undifferentiated (or stem) cell, which can then, in response to environmental and/or mesenchymal changes (beige), differentiate along a different pathway, yielding a distinct phenotype (the dedifferentiation and redifferentiation model). (C) Under normal conditions, the pluripotent stem cells give rise to terminal differentiated cells of a particular phenotype; environmental changes may induce such stem cells to undergo an alternative pathway of differentiation. The recently demonstrated plasticity of certain stem cells, in response to strong mesenchymal niche influence, may fit this model (pluripotent or plastic stem cell model). (D) The tissue contains two separate populations of stem cells: one of them normally gives rise to the (dominant population of) terminally differentiated cell types, whereas the other lays dormant. Environmental changes, including the alteration of the stem cell niche, suppress the growth and differentiation of the originally dominant stem cell (yellow) while activating the originally dormant stem cell (red) that now gives rise to an entirely different phenotype (the selective expansion model). The activation of the esophageal gland stem cell in Barrett's esophagus (Gillen et al., 1988; Kumagai et al., 2003), the vitamin A deficiency–induced squamous metaplasia of tracheal epithelium (Wolbach and Howe, 1925; Nasiell, 1963), uterine epithelium (Ponnamperuma et al., 1999), and cervical epithelium (Darwiche et al., 1993) may fall into this category. (E) The tissue contains two separate cell lineages that occupy different domains separated with well-defined boundaries. Environmental changes such as vitamin A deficiency favor the expansion of one cell lineage over another, thus allowing one cell type to expand and invade into another cell lineage's domain (the cell lineage heterogeneity and replacement model). This last model can best explain our data on urothelial keratinizing squamous metaplasia that is induced by vitamin A deficiency. (C–E) The parallel red bars denote that the process/pathway is blocked. SC, stem cell.

Mentions: There are several possible mechanisms (which are schematically illustrated in Fig. 6) that can potentially explain the striking heterogeneity in urothelial metaplasia and the sharp boundary between the keratinized epithelium and the seemingly normal urothelium. Because we have not found any intermediate cells expressing both urothelial and keratinization markers, we can largely rule out the direct transformation of umbrella cells (Fig. 6 A) or the dedifferentiation of umbrella cells followed by redifferentiation (Fig. 6 B). Given our current finding that there are several distinct urothelial lineages likely to be maintained by separate stem cells, our data are inconsistent with the idea that the entire urinary tract is populated by a single population of pluripotent urothelial stem cells that give rise to different normal urothelia as well as to the keratinized epithelium during vitamin A deficiency (Fig. 6 C). On the other hand, we cannot rule out the possibility that within the proximal urethral urothelium, there exist two separate populations of basal (stem) cells. Because we observed multiple small foci of keratinization in urethral urothelium (Fig. 5), our results are consistent with the presence of some (K14 positive) basal cells within the urethral urothelium that are scattered and intermingled with normal (K14 negative) urothelial basal cells (Fig. 4, i–k); these K14-positive cells are activated during vitamin A deficiency to give rise to a keratinized epithelium (Fig. 6 D). We speculate that the K14-positive basal cells are responsible for the formation of the keratinized foci because only a small number of basal cells are K14 positive in normal urethral urothelium, similar to the keratinized foci. The fact that most of the basal cells are K1/K10 positive practically rules out the possibility that all of these K1/K10-positive cells are stem cells. This situation is analogous to the corneal/limbal epithelium, in which the limbal stem cells are K14 positive and K3/K12 (equivalent to K1/K10 of the keratinized epithelia) negative, whereas the central corneal epithelial basal cells (that are probably transit-amplifying cells) are K14 negative and K3/K12 positive (Schermer et al., 1986; Cotsarelis et al., 1989). Therefore, it is possible that proximal urethral urothelium contains a subpopulation of K14-positive (and K1/K10 negative) basal cells that are selectively activated during vitamin A deficiency, forming keratinized foci (Fig. 6 D) that later fuse and expand. In addition, our results on vitamin A–deficient mice suggest that keratinizing squamous metaplasia originates from the urothelium of the proximal urethra and trigone area and that this keratinized epithelium expands into other parts of the bladder (Figs. 6 E, 3 m, and Table II). This idea is supported by the finding that the proximal urethra–originated keratinized epithelium seems to always maintain a sharp boundary with the normal-looking “retreating” urothelium (Fig. 3). A related finding was made by Varley et al. (2004), who described a sharp boundary between normal-appearing transitional epithelium (K20+, K14−, and K13 basal/intermediate) and squamous epithelium in the human bladder (K20−, K14+, and K13 suprabasal). Overall, our data can best be explained by urothelial heterogeneity in combination with the model in Fig. 6 E, although the model in Fig. 6 D may operate in the initial formation of keratinized foci in the proximal urethral urothelium.


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)

Models of epithelial metaplasia. (A) A terminally differentiated cell (DC; square) can, in response to environmental changes (gray), directly transform into a different type of terminally differentiated cell (diamond; the transdifferentiation model). (B) The terminally differentiated cells can convert back to a relatively undifferentiated (or stem) cell, which can then, in response to environmental and/or mesenchymal changes (beige), differentiate along a different pathway, yielding a distinct phenotype (the dedifferentiation and redifferentiation model). (C) Under normal conditions, the pluripotent stem cells give rise to terminal differentiated cells of a particular phenotype; environmental changes may induce such stem cells to undergo an alternative pathway of differentiation. The recently demonstrated plasticity of certain stem cells, in response to strong mesenchymal niche influence, may fit this model (pluripotent or plastic stem cell model). (D) The tissue contains two separate populations of stem cells: one of them normally gives rise to the (dominant population of) terminally differentiated cell types, whereas the other lays dormant. Environmental changes, including the alteration of the stem cell niche, suppress the growth and differentiation of the originally dominant stem cell (yellow) while activating the originally dormant stem cell (red) that now gives rise to an entirely different phenotype (the selective expansion model). The activation of the esophageal gland stem cell in Barrett's esophagus (Gillen et al., 1988; Kumagai et al., 2003), the vitamin A deficiency–induced squamous metaplasia of tracheal epithelium (Wolbach and Howe, 1925; Nasiell, 1963), uterine epithelium (Ponnamperuma et al., 1999), and cervical epithelium (Darwiche et al., 1993) may fall into this category. (E) The tissue contains two separate cell lineages that occupy different domains separated with well-defined boundaries. Environmental changes such as vitamin A deficiency favor the expansion of one cell lineage over another, thus allowing one cell type to expand and invade into another cell lineage's domain (the cell lineage heterogeneity and replacement model). This last model can best explain our data on urothelial keratinizing squamous metaplasia that is induced by vitamin A deficiency. (C–E) The parallel red bars denote that the process/pathway is blocked. SC, stem cell.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171294&req=5

fig6: Models of epithelial metaplasia. (A) A terminally differentiated cell (DC; square) can, in response to environmental changes (gray), directly transform into a different type of terminally differentiated cell (diamond; the transdifferentiation model). (B) The terminally differentiated cells can convert back to a relatively undifferentiated (or stem) cell, which can then, in response to environmental and/or mesenchymal changes (beige), differentiate along a different pathway, yielding a distinct phenotype (the dedifferentiation and redifferentiation model). (C) Under normal conditions, the pluripotent stem cells give rise to terminal differentiated cells of a particular phenotype; environmental changes may induce such stem cells to undergo an alternative pathway of differentiation. The recently demonstrated plasticity of certain stem cells, in response to strong mesenchymal niche influence, may fit this model (pluripotent or plastic stem cell model). (D) The tissue contains two separate populations of stem cells: one of them normally gives rise to the (dominant population of) terminally differentiated cell types, whereas the other lays dormant. Environmental changes, including the alteration of the stem cell niche, suppress the growth and differentiation of the originally dominant stem cell (yellow) while activating the originally dormant stem cell (red) that now gives rise to an entirely different phenotype (the selective expansion model). The activation of the esophageal gland stem cell in Barrett's esophagus (Gillen et al., 1988; Kumagai et al., 2003), the vitamin A deficiency–induced squamous metaplasia of tracheal epithelium (Wolbach and Howe, 1925; Nasiell, 1963), uterine epithelium (Ponnamperuma et al., 1999), and cervical epithelium (Darwiche et al., 1993) may fall into this category. (E) The tissue contains two separate cell lineages that occupy different domains separated with well-defined boundaries. Environmental changes such as vitamin A deficiency favor the expansion of one cell lineage over another, thus allowing one cell type to expand and invade into another cell lineage's domain (the cell lineage heterogeneity and replacement model). This last model can best explain our data on urothelial keratinizing squamous metaplasia that is induced by vitamin A deficiency. (C–E) The parallel red bars denote that the process/pathway is blocked. SC, stem cell.
Mentions: There are several possible mechanisms (which are schematically illustrated in Fig. 6) that can potentially explain the striking heterogeneity in urothelial metaplasia and the sharp boundary between the keratinized epithelium and the seemingly normal urothelium. Because we have not found any intermediate cells expressing both urothelial and keratinization markers, we can largely rule out the direct transformation of umbrella cells (Fig. 6 A) or the dedifferentiation of umbrella cells followed by redifferentiation (Fig. 6 B). Given our current finding that there are several distinct urothelial lineages likely to be maintained by separate stem cells, our data are inconsistent with the idea that the entire urinary tract is populated by a single population of pluripotent urothelial stem cells that give rise to different normal urothelia as well as to the keratinized epithelium during vitamin A deficiency (Fig. 6 C). On the other hand, we cannot rule out the possibility that within the proximal urethral urothelium, there exist two separate populations of basal (stem) cells. Because we observed multiple small foci of keratinization in urethral urothelium (Fig. 5), our results are consistent with the presence of some (K14 positive) basal cells within the urethral urothelium that are scattered and intermingled with normal (K14 negative) urothelial basal cells (Fig. 4, i–k); these K14-positive cells are activated during vitamin A deficiency to give rise to a keratinized epithelium (Fig. 6 D). We speculate that the K14-positive basal cells are responsible for the formation of the keratinized foci because only a small number of basal cells are K14 positive in normal urethral urothelium, similar to the keratinized foci. The fact that most of the basal cells are K1/K10 positive practically rules out the possibility that all of these K1/K10-positive cells are stem cells. This situation is analogous to the corneal/limbal epithelium, in which the limbal stem cells are K14 positive and K3/K12 (equivalent to K1/K10 of the keratinized epithelia) negative, whereas the central corneal epithelial basal cells (that are probably transit-amplifying cells) are K14 negative and K3/K12 positive (Schermer et al., 1986; Cotsarelis et al., 1989). Therefore, it is possible that proximal urethral urothelium contains a subpopulation of K14-positive (and K1/K10 negative) basal cells that are selectively activated during vitamin A deficiency, forming keratinized foci (Fig. 6 D) that later fuse and expand. In addition, our results on vitamin A–deficient mice suggest that keratinizing squamous metaplasia originates from the urothelium of the proximal urethra and trigone area and that this keratinized epithelium expands into other parts of the bladder (Figs. 6 E, 3 m, and Table II). This idea is supported by the finding that the proximal urethra–originated keratinized epithelium seems to always maintain a sharp boundary with the normal-looking “retreating” urothelium (Fig. 3). A related finding was made by Varley et al. (2004), who described a sharp boundary between normal-appearing transitional epithelium (K20+, K14−, and K13 basal/intermediate) and squamous epithelium in the human bladder (K20−, K14+, and K13 suprabasal). Overall, our data can best be explained by urothelial heterogeneity in combination with the model in Fig. 6 E, although the model in Fig. 6 D may operate in the initial formation of keratinized foci in the proximal urethral urothelium.

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