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Multiple cellular responses to serotonin contribute to epithelial homeostasis.

Pai VP, Horseman ND - PLoS ONE (2011)

Bottom Line: Specifically, serotonin's roles in regulating cell shedding, apoptosis and barrier function of the epithelium.However, upon sustained exposure, serotonin induces apoptosis in the replenishing cell population, causing irreversible changes to the epithelial membrane.The staggered nature of these events induced by serotonin slowly shifts the balance in the epithelium from reversible to irreversible.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.

ABSTRACT
Epithelial homeostasis incorporates the paradoxical concept of internal change (epithelial turnover) enabling the maintenance of anatomical status quo. Epithelial cell differentiation and cell loss (cell shedding and apoptosis) form important components of epithelial turnover. Although the mechanisms of cell loss are being uncovered the crucial triggers that modulate epithelial turnover through regulation of cell loss remain undetermined. Serotonin is emerging as a common autocrine-paracine regulator in epithelia of multiple organs, including the breast. Here we address whether serotonin affects epithelial turnover. Specifically, serotonin's roles in regulating cell shedding, apoptosis and barrier function of the epithelium. Using in vivo studies in mouse and a robust model of differentiated human mammary duct epithelium (MCF10A), we show that serotonin induces mammary epithelial cell shedding and disrupts tight junctions in a reversible manner. However, upon sustained exposure, serotonin induces apoptosis in the replenishing cell population, causing irreversible changes to the epithelial membrane. The staggered nature of these events induced by serotonin slowly shifts the balance in the epithelium from reversible to irreversible. These finding have very important implications towards our ability to control epithelial regeneration and thus address pathologies of aberrant epithelial turnover, which range from degenerative disorders (e.g.; pancreatitis and thyrioditis) to proliferative disorders (e.g.; mastitis, ductal ectasia, cholangiopathies and epithelial cancers).

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Related in: MedlinePlus

Local 5-HT regulates milk stasis– induced epithelial cell shedding.(A) Contralateral mammary gland number 4 from lactating wild type and TPH1 −/− mice after teat-sealing. The glands were harvested 48 h after teat-sealing. Wild type sealed glands show large number of shed cells (most undergoing anoikis) in the alveoli (black arrowheads). Shed cells were rare in sealed TPH1 −/− glands. (B) Quantification of numbers of cells shed into the lumen per alveolus from 5 different alveoli each from 5 independent glands. Data are represented as mean +/− S.E.M.
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pone-0017028-g001: Local 5-HT regulates milk stasis– induced epithelial cell shedding.(A) Contralateral mammary gland number 4 from lactating wild type and TPH1 −/− mice after teat-sealing. The glands were harvested 48 h after teat-sealing. Wild type sealed glands show large number of shed cells (most undergoing anoikis) in the alveoli (black arrowheads). Shed cells were rare in sealed TPH1 −/− glands. (B) Quantification of numbers of cells shed into the lumen per alveolus from 5 different alveoli each from 5 independent glands. Data are represented as mean +/− S.E.M.

Mentions: In the context of lactation, the mammary epithelium was highly active and columnar in appearance (Figure 1A WT open). Minimal to undetectable amounts of cell shedding, and no noticeable apoptosis was observed in the epithelium during lactation (Figure1A WT open and Figure 1B). In the involuting glands (sealed) there was a dramatic increase in the epithelial cells being shed into the lumen (Fig. 1A WT sealed black arrowheads and Figure 1B). Since, only local factors are brought into play at this point, it suggests that cell shedding is induced by local factors. In order to address whether 5-HT affects cell shedding we performed teat-sealing in TPH1 knockout mice. Sealed TPH1−/− mice failed to show the characteristic increase in shed cells (Figure 1A TPH−/− sealed and Figure 1B). Thus, absence of 5-HT is associated with absence of cells shed into the lumen. This suggested that 5-HT was involved in regulating the cell shedding seen in response to milk stasis and involution. Note that all the glands depicted were still in the reversible phase of involution [31], [32].


Multiple cellular responses to serotonin contribute to epithelial homeostasis.

Pai VP, Horseman ND - PLoS ONE (2011)

Local 5-HT regulates milk stasis– induced epithelial cell shedding.(A) Contralateral mammary gland number 4 from lactating wild type and TPH1 −/− mice after teat-sealing. The glands were harvested 48 h after teat-sealing. Wild type sealed glands show large number of shed cells (most undergoing anoikis) in the alveoli (black arrowheads). Shed cells were rare in sealed TPH1 −/− glands. (B) Quantification of numbers of cells shed into the lumen per alveolus from 5 different alveoli each from 5 independent glands. Data are represented as mean +/− S.E.M.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044750&req=5

pone-0017028-g001: Local 5-HT regulates milk stasis– induced epithelial cell shedding.(A) Contralateral mammary gland number 4 from lactating wild type and TPH1 −/− mice after teat-sealing. The glands were harvested 48 h after teat-sealing. Wild type sealed glands show large number of shed cells (most undergoing anoikis) in the alveoli (black arrowheads). Shed cells were rare in sealed TPH1 −/− glands. (B) Quantification of numbers of cells shed into the lumen per alveolus from 5 different alveoli each from 5 independent glands. Data are represented as mean +/− S.E.M.
Mentions: In the context of lactation, the mammary epithelium was highly active and columnar in appearance (Figure 1A WT open). Minimal to undetectable amounts of cell shedding, and no noticeable apoptosis was observed in the epithelium during lactation (Figure1A WT open and Figure 1B). In the involuting glands (sealed) there was a dramatic increase in the epithelial cells being shed into the lumen (Fig. 1A WT sealed black arrowheads and Figure 1B). Since, only local factors are brought into play at this point, it suggests that cell shedding is induced by local factors. In order to address whether 5-HT affects cell shedding we performed teat-sealing in TPH1 knockout mice. Sealed TPH1−/− mice failed to show the characteristic increase in shed cells (Figure 1A TPH−/− sealed and Figure 1B). Thus, absence of 5-HT is associated with absence of cells shed into the lumen. This suggested that 5-HT was involved in regulating the cell shedding seen in response to milk stasis and involution. Note that all the glands depicted were still in the reversible phase of involution [31], [32].

Bottom Line: Specifically, serotonin's roles in regulating cell shedding, apoptosis and barrier function of the epithelium.However, upon sustained exposure, serotonin induces apoptosis in the replenishing cell population, causing irreversible changes to the epithelial membrane.The staggered nature of these events induced by serotonin slowly shifts the balance in the epithelium from reversible to irreversible.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.

ABSTRACT
Epithelial homeostasis incorporates the paradoxical concept of internal change (epithelial turnover) enabling the maintenance of anatomical status quo. Epithelial cell differentiation and cell loss (cell shedding and apoptosis) form important components of epithelial turnover. Although the mechanisms of cell loss are being uncovered the crucial triggers that modulate epithelial turnover through regulation of cell loss remain undetermined. Serotonin is emerging as a common autocrine-paracine regulator in epithelia of multiple organs, including the breast. Here we address whether serotonin affects epithelial turnover. Specifically, serotonin's roles in regulating cell shedding, apoptosis and barrier function of the epithelium. Using in vivo studies in mouse and a robust model of differentiated human mammary duct epithelium (MCF10A), we show that serotonin induces mammary epithelial cell shedding and disrupts tight junctions in a reversible manner. However, upon sustained exposure, serotonin induces apoptosis in the replenishing cell population, causing irreversible changes to the epithelial membrane. The staggered nature of these events induced by serotonin slowly shifts the balance in the epithelium from reversible to irreversible. These finding have very important implications towards our ability to control epithelial regeneration and thus address pathologies of aberrant epithelial turnover, which range from degenerative disorders (e.g.; pancreatitis and thyrioditis) to proliferative disorders (e.g.; mastitis, ductal ectasia, cholangiopathies and epithelial cancers).

Show MeSH
Related in: MedlinePlus