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Investigating Progesterone Resistance in Endometriosis Using Menstrual Effluent- Derived Endometrial Stromal Cells.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Investigating Progesterone Resistance in Endometriosis Using Menstrual Effluent- Derived Endometrial Stromal Cells./
Author:	Moss, Matthew Adam.
Description:	1 online resource (459 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
Contained By:	Dissertations Abstracts International85-12B.
Subject:	Molecular biology. -
Online resource:	click for full text (PQDT)
ISBN:	9798382810058

Investigating Progesterone Resistance in Endometriosis Using Menstrual Effluent- Derived Endometrial Stromal Cells.
Moss, Matthew Adam.

Investigating Progesterone Resistance in Endometriosis Using Menstrual Effluent- Derived Endometrial Stromal Cells. - 1 online resource (459 pages)

Source: Dissertations Abstracts International, Volume: 85-12, Section: B.

Thesis (Ph.D.)--Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 2024.

Includes bibliographical references

Introduction: Endometriosis is a condition that affects approximately 10% of people with uteruses. This condition is defined by the growth of endometrial-like cells outside of the uterus, mainly in the abdominal cavity. Endometriosis is characterized primarily by pain before, during, and after menstruation, pain with urination and sexual intercourse, and infertility. At the molecular level, the condition is characterized by overexpression of estrogen (E2) and resistance to progesterone (P4) (or reduced sensitivity of P4). P4-resistance is likely related to decidualization defects found in endometriosis patients and associated infertility. Importantly, one of the most common palliative treatments for endometriosis patients are progestins, which are molecules that mimic the effects of progesterone by binding to the progesterone receptors (PRs). Progestins are often ineffective, likely due to the progesterone resistance phenotype. In the current study, we probe the mechanism of action of the PRs using endometrial stromal cells in order to identify deficiencies that may be related to P4-resistance.Methods: Menstrual effluent-derived endometrial stromal cells (ME-eSCs) cultured from control (CTRL) and endometriosis (ENDO) subjects were subjected to translocation assays by imaging flow cytometry in order to assess rapid (1hr) translocation of PR following treatment with medroxyprogesterone acetate (MPA), a synthetic and clinically used progestin. This MPA response was probed by bulk RNA-sequencing. CUT&RUN sequencing was used to determine levels of PR binding to genes associated with this early MPA response, and also global epigenetic response. Single cell RNA-sequencing was used to probe the downstream effects of this treatment in cultured ME-eSCs cultured from controls and endometriosis subjects.Results: ME-eSCs from donors with endometriosis showed decreased nuclear translocation of PR-B following MPA treatment when compared to those from unaffected control donors. This was associated with MPA-induced blunted gene expression responses in eSCs from patients with endometriosis vs. controls. Additionally, there were differential gene expression profiles in ENDO-eSCs when compared to CTRL-eSCs under basal conditions. PR-B binding was increased by MPA in CTRL-eSCs, but not ENDO-eSCs, particularly at promoter regions. MPA induced substantial changes in the active chromatin landscape of both CTRL-eSCs and ENDO-eSCs, though fewer changes were observed in ENDO-eSCs. The changes which were exclusive to CTRL-eSCs were associated with processes that regulate apoptosis and extracellular matrix changes. After 24 hours of MPA stimulation, eSCs undergo substantial cell state composition and whole transcriptome changes. These were more dominant in CTRL-eSCs than ENDO-eSCs and were related to both extracellular matrix and apoptotic processes.Conclusions: ME-eSCs are a reliable model to study progesterone sensitivity in the setting of endometriosis. Investigating the effects of progestins on ME-eSCs revealed that progestin-induced nuclear translocation of PR-B was significantly reduced in eSCs derived from endometriosis patients when compared to eSCs from unaffected controls. Similarly, progestin-induced gene expression was reduced in ENDO-eSCs vs. CTRL-eSCs. PR-B binding is reduced in ENDO-eSCs relative to CTRL-eSCs in a way associated with the gene expression differences in these cells. These changes are associated with epigenomic changes, and also are sustained at the transcriptomic level after longer treatments, in addition to the changes downstream of them. It is also possible to use tissue from menstrual effluent without culturing to assess these differences in gene expression in a rapid and potentially clinical useful way. Together, these findings support future studies 1) to develop methods for assessing patients' P4 sensitivity in the clinic to help tailor progestin therapy and 2) to better define the causative mechanism(s) underlying P4 resistance that could be targeted to improve progesterone sensitivity in endometriosis patients, particularly those with infertility.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798382810058Subjects--Topical Terms:

583443
Molecular biology.
Subjects--Index Terms:

EndometriosisIndex Terms--Genre/Form:

554714
Electronic books.

Investigating Progesterone Resistance in Endometriosis Using Menstrual Effluent- Derived Endometrial Stromal Cells.
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520 $a Introduction: Endometriosis is a condition that affects approximately 10% of people with uteruses. This condition is defined by the growth of endometrial-like cells outside of the uterus, mainly in the abdominal cavity. Endometriosis is characterized primarily by pain before, during, and after menstruation, pain with urination and sexual intercourse, and infertility. At the molecular level, the condition is characterized by overexpression of estrogen (E2) and resistance to progesterone (P4) (or reduced sensitivity of P4). P4-resistance is likely related to decidualization defects found in endometriosis patients and associated infertility. Importantly, one of the most common palliative treatments for endometriosis patients are progestins, which are molecules that mimic the effects of progesterone by binding to the progesterone receptors (PRs). Progestins are often ineffective, likely due to the progesterone resistance phenotype. In the current study, we probe the mechanism of action of the PRs using endometrial stromal cells in order to identify deficiencies that may be related to P4-resistance.Methods: Menstrual effluent-derived endometrial stromal cells (ME-eSCs) cultured from control (CTRL) and endometriosis (ENDO) subjects were subjected to translocation assays by imaging flow cytometry in order to assess rapid (1hr) translocation of PR following treatment with medroxyprogesterone acetate (MPA), a synthetic and clinically used progestin. This MPA response was probed by bulk RNA-sequencing. CUT&RUN sequencing was used to determine levels of PR binding to genes associated with this early MPA response, and also global epigenetic response. Single cell RNA-sequencing was used to probe the downstream effects of this treatment in cultured ME-eSCs cultured from controls and endometriosis subjects.Results: ME-eSCs from donors with endometriosis showed decreased nuclear translocation of PR-B following MPA treatment when compared to those from unaffected control donors. This was associated with MPA-induced blunted gene expression responses in eSCs from patients with endometriosis vs. controls. Additionally, there were differential gene expression profiles in ENDO-eSCs when compared to CTRL-eSCs under basal conditions. PR-B binding was increased by MPA in CTRL-eSCs, but not ENDO-eSCs, particularly at promoter regions. MPA induced substantial changes in the active chromatin landscape of both CTRL-eSCs and ENDO-eSCs, though fewer changes were observed in ENDO-eSCs. The changes which were exclusive to CTRL-eSCs were associated with processes that regulate apoptosis and extracellular matrix changes. After 24 hours of MPA stimulation, eSCs undergo substantial cell state composition and whole transcriptome changes. These were more dominant in CTRL-eSCs than ENDO-eSCs and were related to both extracellular matrix and apoptotic processes.Conclusions: ME-eSCs are a reliable model to study progesterone sensitivity in the setting of endometriosis. Investigating the effects of progestins on ME-eSCs revealed that progestin-induced nuclear translocation of PR-B was significantly reduced in eSCs derived from endometriosis patients when compared to eSCs from unaffected controls. Similarly, progestin-induced gene expression was reduced in ENDO-eSCs vs. CTRL-eSCs. PR-B binding is reduced in ENDO-eSCs relative to CTRL-eSCs in a way associated with the gene expression differences in these cells. These changes are associated with epigenomic changes, and also are sustained at the transcriptomic level after longer treatments, in addition to the changes downstream of them. It is also possible to use tissue from menstrual effluent without culturing to assess these differences in gene expression in a rapid and potentially clinical useful way. Together, these findings support future studies 1) to develop methods for assessing patients' P4 sensitivity in the clinic to help tailor progestin therapy and 2) to better define the causative mechanism(s) underlying P4 resistance that could be targeted to improve progesterone sensitivity in endometriosis patients, particularly those with infertility.
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653 $a Progesterone receptor
653 $a Progesterone resistance
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