Pluripotent stem cell-derived endometrial stromal fibroblasts in a cyclic, hormone-responsive, coculture model of human decidua

Cheung, Virginia Chu; Peng, Chian Yu; Marinić, Mirna; Sakabe, Noboru Jo; Aneas, Ivy; Lynch, Vincent J.; Ober, Carole; Nóbrega, Marcelo A.; Kessler, John A.

doi:10.1016/j.celrep.2021.109138

Cited by 39 publications

(27 citation statements)

References 63 publications

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“…Here we report on the development of endometrial assembloids, consisting of gland-like organoids surrounded by a matrix rich in primary EnSC, as novel model to parse the cellular dynamics that govern embryo implantation in cycling human endometrium. While assembloids complement and advance other recently described endometrial organoid models ( Boretto et al, 2017 ; Cheung et al, 2021 ; Fitzgerald et al, 2019 ; Luddi et al, 2020 ; Turco et al, 2017 ), they still lack the cellular complexity of native endometrium, including uNK cells, macrophages, and vascular cells. Nevertheless, we demonstrated that aspects of pathological implantation events can be recapitulated in assembloids, rendering them useful as novel models to study mechanisms of reproductive failure and evaluate potential therapeutic interventions.…”

Section: Discussionmentioning

confidence: 94%

“…Based on these insights, we hypothesized that acute senescence is integral to successful implantation by creating conditions for anchorage of the conceptus in an otherwise tightly adherent decidual matrix. To test this hypothesis, we developed an ‘assembloid’ model, consisting of endometrial gland-like organoids and primary EnSC, which recapitulates the complexity in cell states and gene expression of the midluteal implantation window, improving resemblance to endometrial tissue in comparison with existing co-culture models ( Cheung et al, 2021 ; Rawlings, 2021 ). We used this model to establish co-cultures with human blastocysts and demonstrate that aspects of different pathological states associated with implantation failure and miscarriage can be recapitulated in endometrial assembloids by modulating decidual senescence.…”

Section: Introductionmentioning

confidence: 99%

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Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids

Rawlings

Makwana

Taylor

et al. 2021

eLife

139

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Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterised endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids

Rawlings

Makwana

Taylor

et al. 2021

eLife

139

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“…Good screens for potential toxicity might help to obviate this problem. Organoid models of the human endometrium have been developed ( Turco et al, 2018 ; Chu Cheung et al, 2021 ), and ultimately co-culture models of iTSC with endometrial organoids would be most useful for this purpose.…”

Section: Discussionmentioning

confidence: 99%

Establishment of human induced trophoblast stem-like cells from term villous cytotrophoblasts

et al. 2021

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Human trophoblast stem cells (hTSC) can be isolated from first trimester placenta but not from term placenta. Here we demonstrate that villous cytotrophoblasts (vCTB) from term placenta can be reprogrammed into induced trophoblastic stem-like cells (iTSC) by introducing sets of transcription factors. The iTSCs express TSC markers such as GATA3, TEAD4 and ELF5, and are multipotent, validated by their differentiation into both extravillous trophoblasts (EVT) and syncytiotrophoblasts (STB) in vitro and in vivo . The iTSC can be passaged indefinitely in vitro without slowing of growth. The transcriptome profile of these cells closely resembles the profile of hTSC isolated from first trimester placentae but different from the term placental vCTB from which they originated. The ability to reprogram cells from term placenta into iTSC will allow study of early gestation events which impact placental function later in gestation, including preeclampsia and spontaneous preterm birth.

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“…These drugs can be broadly categorised into two categories: pharmacological agents termed "senolytics, " which eliminate senescent cells, and "senomorphics, " which prevent the detrimental cell-extrinsic effects of senescent cells and include SASP inhibitors (63,151). Further, organoid and assembloid technologies now enable rapid screening of the effectiveness of drugs in restoring or enhancing the implantation environment (18,(152)(153)(154). Altogether, a new age of nonhormonal "endometrial therapeutics" appears just around the corner.…”

Section: Summary and Therapeutic Perspectivementioning

confidence: 99%

The Role of Decidual Subpopulations in Implantation, Menstruation and Miscarriage

Muter

Kong

Brosens

2021

Front. Reprod. Health

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In each menstrual cycle, the endometrium becomes receptive to embryo implantation while preparing for tissue breakdown and repair. Both pregnancy and menstruation are dependent on spontaneous decidualization of endometrial stromal cells, a progesterone-dependent process that follows rapid, oestrogen-dependent proliferation. During the implantation window, stromal cells mount an acute stress response, which leads to the emergence of functionally distinct decidual subsets, reflecting the level of replication stress incurred during the preceding proliferative phase. Progesterone-dependent, anti-inflammatory decidual cells (DeC) form a robust matrix that accommodates the conceptus whereas pro-inflammatory, progesterone-resistant stressed and senescent decidual cells (senDeC) control tissue remodelling and breakdown. To execute these functions, each decidual subset engages innate immune cells: DeC partner with uterine natural killer (uNK) cells to eliminate senDeC, while senDeC co-opt neutrophils and macrophages to assist with tissue breakdown and repair. Thus, successful transformation of cycling endometrium into the decidua of pregnancy not only requires continuous progesterone signalling but dominance of DeC over senDeC, aided by recruitment and differentiation of circulating NK cells and bone marrow-derived decidual progenitors. We discuss how the frequency of cycles resulting in imbalanced decidual subpopulations may determine the recurrence risk of miscarriage and highlight emerging therapeutic strategies.

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Pluripotent stem cell-derived endometrial stromal fibroblasts in a cyclic, hormone-responsive, coculture model of human decidua

Cited by 39 publications

References 63 publications

Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids

Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids

Establishment of human induced trophoblast stem-like cells from term villous cytotrophoblasts

The Role of Decidual Subpopulations in Implantation, Menstruation and Miscarriage

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