COX2 is induced in the ovarian epithelium during ovulatory wound repair and promotes cell survival†

Carter, Lauren E.; Cook, David P.; Collins, Olga; Gamwell, Lisa F; Dempster, Holly A; Wong, Howard W; McCloskey, Curtis W.; Garson, Ken; Vuong, Nhung; Vanderhyden, Barbara C.

doi:10.1093/biolre/ioz134

Cited by 12 publications

(13 citation statements)

References 55 publications

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“…WNT4 and WNT5a have been found to play crucial roles during follicle development and ovulation [23][24][25] and we have explored here their roles during ovulatory wound repair. Our evidence suggests WNT5a, but not WNT4, regulates cell morphology, proliferation, and migration and stimulates the expression of Cd44, Vim, Snail, Ptgs2 and Alcam, all markers of mesenchymal cells 26,32,33 , implicating WNT5a as a possible autocrine regulator of epithelial cells undergoing EMT. Previously, Wnt5a was identified as a gene whose expression was increased by TGFβ1 in mammary epithelial cells, and is required for the TGFβ1-mediated inhibition of ductal extension in vivo and branching in vitro 34 .…”

Section: Discussionmentioning

confidence: 67%

“…Previously, Wnt5a was identified as a gene whose expression was increased by TGFβ1 in mammary epithelial cells, and is required for the TGFβ1-mediated inhibition of ductal extension in vivo and branching in vitro 34 . We have recently shown that treating primary cultures of OSE cells with TGFβ1 induced an EMT mediated by TGFβ1 signaling, and the transcription factor Snail was the only EMT-associated transcription factor tested that was increased by TGFβ1 26 . RNA-seq analysis of those cells showed that TGFβ1 up-regulates Wnt5a mRNA expression in OSE cells.…”

Section: Discussionmentioning

confidence: 99%

“…WNT5a and TGFβ1 regulate EMT via different mechanisms. We have previously reported that TGFβ1 promotes ovulatory wound repair in mice by induction of an EMT in OSE cells 26 . Further analysis of www.nature.com/scientificreports www.nature.com/scientificreports/ the RNA-seq data revealed a large number of WNT-associated genes, including Wnt5a, and WNT signaling was one of the top pathways associated with TGFβ1 treatment ( Figure S1).…”

Section: Deletion Of Wnt5a In the Ose Stimulates Active-ctnnb1 Expresmentioning

confidence: 98%

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Non-canonical WNT5a regulates Epithelial-to-Mesenchymal Transition in the mouse ovarian surface epithelium

Abedini

Sayed

Carter

et al. 2020

Sci Rep

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The ovarian surface epithelium (OSE) is a monolayer that covers the ovarian surface and is involved in ovulation by rupturing and enabling release of a mature oocyte and by repairing the wound after ovulation. Epithelial-to-mesenchymal transition (EMT) is a mechanism that may promote wound healing after ovulation. While this process is poorly understood in the OSE, in other tissues wound repair is known to be under the control of the local microenvironment and different growth factors such as the WNT signaling pathway. Among WNT family members, WNT4 and WNT5a are expressed in the OSE and are critical for the ovulatory process. The objective of this study was to determine the potential roles of WNT4 and WNT5a in regulating the OSE layer. Using primary cultures of mouse OSE cells, we found WNT5a, but not WNT4, promotes EMT through a non-canonical Ca 2+-dependent pathway, upregulating the expression of Vimentin and CD44, enhancing cell migration, and inhibiting the CTNNB1 pathway and proliferation. We conclude that WNT5a is a stimulator of the EMT in OSE cells, and acts by suppressing canonical WNT signaling activity and inducing the non-canonical Ca 2+ pathway.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Deletion Of Wnt5a In the Ose Stimulates Active-ctnnb1 Expresmentioning

confidence: 98%

See 1 more Smart Citation

Non-canonical WNT5a regulates Epithelial-to-Mesenchymal Transition in the mouse ovarian surface epithelium

Abedini

Sayed

Carter

et al. 2020

Sci Rep

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“…COX2 expression increases following the LH surge and is expressed in the granulosa cells of pre-ovulatory follicles [52]. COX2 also plays a role following ovulation, in that it is upregulated during the EMT, a process involved in wound repair that is induced in the OSE following ovulation [53]. Based on its broad roles prior to ovulation and during wound repair, we questioned whether there were age-associated differences in COX2 expression in the ovary.…”

Section: Decreased Cox2 Expression May Be a Mechanism For Ovulatory Amentioning

confidence: 99%

Ovulation and ovarian wound healing are impaired with advanced reproductive age

Mara

Zhou

Larmore

et al. 2020

Aging

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Aging is associated with reduced tissue remodeling efficiency and increased fibrosis, characterized by excess collagen accumulation and altered matrix degradation. Ovulation, the process by which an egg is released from the ovary, is one of the most dynamic cycles of tissue wounding and repair. Because the ovary is one of the first organs to age, ovulation and ovarian wound healing is impaired with advanced reproductive age. To test this hypothesis, we induced superovulation in reproductively young and old mice and determined the numbers of eggs ovulated and corpora lutea (CLs), the progesterone producing glands formed post-ovulation. Reproductively old mice ovulated fewer eggs and had fewer CLs relative to young controls. Moreover, reproductively old mice exhibited a greater number of oocytes trapped within CLs and expanded cumulus oocyte complexes within unruptured antral follicles, indicative of failed ovulation. In addition, post-ovulatory tissue remodeling was compromised with age as evidenced by reduced CL vasculature, increased collagen, decreased hyaluronan, decreased cell proliferation and apoptosis, impaired wound healing capacity, and aberrant morphology of the ovarian surface epithelium (OSE). These findings demonstrate that ovulatory dysfunction is an additional mechanism underlying the age-related loss of fertility beyond the reduction of egg quantity and quality.

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“…We have previously demonstrated that mouse OSE (mOSE) cells undergo an EMT and acquire stem cell characteristics when exposed to TGFB1 10,16 . To confirm these findings, we first assessed the ability of TGFB1-treated mOSE cells to form self-renewing spheroids in suspension culture.…”

Section: Cd44 Is a Marker Of Emt-associated Stemness In Ose Cellsmentioning

confidence: 99%

Transcriptional heterogeneity of stemness phenotypes in the ovarian epithelium

Carter

Cook

McCloskey

et al. 2020

Preprint

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The ovarian surface epithelium (OSE) is a monolayer of epithelial cells covering the surface of the ovary. During ovulation, the OSE is ruptured to allow release of the oocyte. This wound is quickly repaired, but mechanisms of this repair are poorly understood. The contribution of tissue-resident stem cells in the homeostasis of several epithelial tissues is widely accepted, such as the intestinal epithelium, airway epithelium, and skin, but their involvement in OSE maintenance is unclear. While putative stem cell populations in the OSE have been described, how they are regulated is poorly defined. We show that traits associated with stem cells (stemness) can be increased in OSE following exposure to the cytokine TGFB1, overexpression of the transcription factor Snai1 , or deletion of Brca1 . By assessing the gene expression profiles of these populations, we show that stemness is often linked to mesenchymal-associated gene expression and higher activation of ERK signalling, but it is not consistently dependent on their activation. Expression profiles of these populations are extremely context specific, suggesting that stemness may not correspond to a single, distinct population, but rather is a heterogenous state that can possibly emerge from diverse environmental cues. Together, these findings support that the OSE may not require distinct stem cell populations for long-term maintenance, and may achieve this through transient dedifferentiation into a stem-like state./

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COX2 is induced in the ovarian epithelium during ovulatory wound repair and promotes cell survival†

Cited by 12 publications

References 55 publications

Non-canonical WNT5a regulates Epithelial-to-Mesenchymal Transition in the mouse ovarian surface epithelium

Non-canonical WNT5a regulates Epithelial-to-Mesenchymal Transition in the mouse ovarian surface epithelium

Ovulation and ovarian wound healing are impaired with advanced reproductive age

Transcriptional heterogeneity of stemness phenotypes in the ovarian epithelium

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