Evolutionary transcriptomics implicates<i>HAND2</i>in the origins of implantation and regulation of gestation length

Marinić, Mirna; Mika, Katelyn; Chigurupati, Sravanthi; Lynch, Vincent J.

doi:10.1101/2020.06.15.152868

Cited by 8 publications

(8 citation statements)

References 175 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Each of these subpopulations expressed marker genes identified previously by scRNA-seq reconstruction of the decidual pathway in standard primary EnSC cultures (Lucas et al, 2020). Pre-decidual cells in SS3 express HAND2, a key decidual transcription factor (Marinic et al, 2021), as well as previously identified genes encoding secreted factors, including VEGFA (vascular endothelial growth factor A), CRISPLD2 (a progesterone-dependent anti-inflammatory response gene coding cysteine rich secretory protein LCCL domain containing 2), IL15 (interleukin 15) and TIMP3 (TIMP metallopeptidase inhibitor 3) (Lucas et al, 2020). Novel candidate pre-decidual genes were also identified, such as DDIT4 (DNA damage inducible transcript 4), encoding a stress response protein intimately involved in autophagy, stemness and antioxidative defences (Ho et al, 2020, Miller et al, 2020.…”

Section: Cellular Complexity Of Decidualizing Assembloids Mimics Midluteal Endometriummentioning

confidence: 85%

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

Rawlings

Makwana

Taylor

et al. 2021

eLife

124

View full text Add to dashboard Cite

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.

show abstract

Section: Cellular Complexity Of Decidualizing Assembloids Mimics Midluteal Endometriummentioning

confidence: 85%

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

Rawlings

Makwana

Taylor

et al. 2021

eLife

124

View full text Add to dashboard Cite

show abstract

“…Increased COUP-TFII expression by PGR-IHH signaling not only results in increased stromal PGR levels but also the levels of stromal heart and neural crest derivatives expressed transcript 2 ( Hand2 ) ( Li et al, 2011 ; Marinic et al, 2021 ; Figure 2A ), which is a basic helix-loop-helix transcription factor. To date, studies have not established whether the COUP-TFII transcription factor directly or indirectly (i.e., via stromal PGR) increases stromal Hand2 levels; however, HAND2 suppresses stromal fibroblast growth factor ( Fgf ) family members ( Fgf −1, −2, −9, and −18) in the endometrium ( Li et al, 2011 ; Figure 2A ).…”

Section: Endometrial Molecular Mediators Of the Progesterone Receptormentioning

confidence: 99%

Illuminating the “Black Box” of Progesterone-Dependent Embryo Implantation Using Engineered Mice

Maurya

DeMayo

Lydon

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Synchrony between progesterone-driven endometrial receptivity and the arrival of a euploid blastocyst is essential for embryo implantation, a prerequisite event in the establishment of a successful pregnancy. Advancement of embryo implantation within the uterus also requires stromal fibroblasts of the endometrium to transform into epithelioid decidual cells, a progesterone-dependent cellular transformation process termed decidualization. Although progesterone is indispensable for these cellular processes, the molecular underpinnings are not fully understood. Because human studies are restricted, much of our fundamental understanding of progesterone signaling in endometrial periimplantation biology comes from in vitro and in vivo experimental systems. In this review, we focus on the tremendous progress attained with the use of engineered mouse models together with high throughput genome-scale analysis in disclosing key signals, pathways and networks that are required for normal endometrial responses to progesterone during the periimplantation period. Many molecular mediators and modifiers of the progesterone response are implicated in cross talk signaling between epithelial and stromal cells of the endometrium, an intercellular communication system that is critical for the ordered spatiotemporal control of embryo invasion within the maternal compartment. Accordingly, derailment of these signaling systems is causally linked with infertility, early embryo miscarriage and gestational complications that symptomatically manifest later in pregnancy. Such aberrant progesterone molecular responses also contribute to endometrial pathologies such as endometriosis, endometrial hyperplasia and cancer. Therefore, our review makes the case that further identification and functional analysis of key molecular mediators and modifiers of the endometrial response to progesterone will not only provide much-needed molecular insight into the early endometrial cellular changes that promote pregnancy establishment but lend credible hope for the development of more effective mechanism-based molecular diagnostics and precision therapies in the clinical management of female infertility, subfertility and a subset of gynecological morbidities.

show abstract

“…Each of these subpopulations expressed marker genes identified previously by scRNA-seq reconstruction of the decidual pathway in standard primary EnSC cultures (Lucas et al, 2020). Pre-decidual cells in SS3 express HAND2 , a key decidual transcription factor (Marinic et al, 2021), as well as previously identified genes encoding secreted factors, including VEGFA (vascular endothelial growth factor A), CRISPLD2 (a progesterone-dependent anti-inflammatory response gene coding cysteine rich secretory protein LCCL domain containing 2) , IL15 (interleukin 15) and TIMP3 (TIMP metallopeptidase inhibitor 3) (Lucas et al, 2020). Novel pre-decidual genes were also identified, such as DDIT4 (DNA damage inducible transcript 4), encoding a stress response protein intimately involved in autophagy, stemness and antioxidative defences (Ho et al, 2020, Miller et al, 2020).…”

Section: Resultsmentioning

confidence: 67%

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

Rawlings

Makwana

Taylor

et al. 2021

Preprint

View full text Add to dashboard Cite

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 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 inhibiting senescence and mesenchymal-epithelial transition, processes involved in endometrial breakdown and regeneration, respectively. Accelerated decidualization resulted in entrapment of co-cultured human blastocysts in a largely 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 demonstrate that senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.

show abstract

Evolutionary transcriptomics implicatesHAND2in the origins of implantation and regulation of gestation length

Cited by 8 publications

References 175 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

Illuminating the “Black Box” of Progesterone-Dependent Embryo Implantation Using Engineered Mice

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

Contact Info

Product

Resources

About