At the beginning of a human pregnancy, the embryo implants into the uterus lining, known as the endometrium. At this point, the endometrium transforms into a new tissue that helps the placenta to form. Problems in this transformation process are linked to pregnancy disorders, many of which can lead to implantation failure (the embryo fails to invade the endometrium altogether) or recurrent miscarriages (the embryo implants successfully, but the interface between the placenta and the endometrium subsequently breaks down).

Studying the implantation of human embryos directly is difficult due to ethical and technical barriers, and animals do not perfectly mimic the human process, making it challenging to determine the causes of pregnancy disorders. However, it is likely that a form of cellular arrest called senescence, in which cells stop dividing but remain metabolically active, plays a role. Indeed, excessive senescence in the cells that make up the endometrium is associated with recurrent miscarriage, while a lack of senescence is associated with implantation failure.

To study this process, Rawlings et al. developed a new laboratory model of the human endometrium by assembling two of the main cell types found in the tissue into a three-dimensional structure. When treated with hormones, these ‘assembloids’ successfully mimic the activity of genes in the cells of the endometrium during implantation. Rawlings et al. then exposed the assembloids to the drug dasatinib, which targets and eliminates senescent cells. This experiment showed that assembloids become very robust and static when devoid of senescent cells.

Rawlings et al. then studied the interaction between embryos and assembloids using time-lapse imaging. In the absence of dasatinib treatment, cells in the assembloid migrated towards the embryo as it expanded, a process required for implantation. However, when senescent cells were eliminated using dasatinib, this movement of cells towards the embryo stopped, and the embryo failed to expand, in a situation that mimicks implantation failure.

The assembloid model of the endometrium may help scientists to study endometrial defects in the lab and test potential treatments. Further work will include other endometrial cell types in the assembloids, and could help increase the reliability of the model. However, any drug treatments identified using this model will need further research into their safety and effectiveness before they can be offered to patients.

Upon embryo implantation, the cycling human endometrium transforms into the decidua of pregnancy to accommodate the placenta (Gellersen and Brosens, 2014). Transition between these physiological endometrial states requires intensive tissue remodelling, a process termed decidualization. Notwithstanding that decidualization in early pregnancy cannot be studied directly, a spectrum of prevalent reproductive disorders is attributed to perturbations in this process, including recurrent implantation failure and recurrent pregnancy loss (Dimitriadis et al., 2020; Macklon, 2017; Zhou et al., 2019). By contrast, the sequence of events that renders the endometrium receptive to embryo implantation has been investigated extensively, starting with obligatory oestrogen-dependent tissue growth following menstrual repair. As a consequence of rapid proliferation of stromal fibroblasts and glandular epithelial cells (EpCs), which peaks in the upper third of the functional layer (Ferenczy et al., 1979), endometrial volume and thickness increases multifold prior to ovulation (Raine-Fenning et al., 2004; Dallenbach-Hellweg, 1981). After the postovulatory rise in progesterone levels, proliferation of EpCs first decreases and then ceases altogether in concert with the onset of apocrine glandular secretions, heralding the start of the midluteal window of implantation (Dallenbach-Hellweg, 1981). Concurrently, uterine natural killer (uNK) cells accumulate and endometrial stromal cells (EnSCs) start decidualizing in a process that can be described as ‘inflammatory programming’ (Brighton et al., 2017; Chavan et al., 2021; Erkenbrack et al., 2018; Salker et al., 2012). Morphological decidual cells, characterized by abundant cytoplasm and enlarged nuclei, emerge upon closure of the 4-day implantation window, meaning that the endometrium has become refractory to embryo implantation (Gellersen and Brosens, 2014). In pregnancy, decidual cells form a robust, tolerogenic matrix in which invading trophoblast cells cooperate with local immune cells to form a haemochorial placenta (Aplin et al., 2020; Vento-Tormo et al., 2018). In non-conception cycles, however, falling progesterone levels and influx of neutrophils lead to breakdown of the superficial endometrial layer and menstrual shedding (Jabbour et al., 2006).

Recently, we highlighted the importance of cellular senescence in endometrial remodelling during the midluteal implantation window (Brighton et al., 2017; Lucas et al., 2020; Kong et al., 2021). Senescence denotes a cellular stress response triggered by replicative exhaustion or other stressors that cause macromolecular damage (Muñoz-Espín and Serrano, 2014). Activation of tumour suppressor pathways and upregulation of cyclin-dependent kinase inhibitors p16^INK4a (encoded by CDKN2A) and p21^CIP1 (CDKN1A) lead to permanent cell cycle arrest, induction of survival genes, and production of a bioactive secretome, referred to as the senescence-associated secretory phenotype (SASP). The composition of the SASP is tissue-specific but typically includes proinflammatory and immunomodulatory cytokines, chemokines, growth factors, and extracellular matrix (ECM) proteins and proteases (Birch and Gil, 2020). Acute senescence, characterized by transient SASP production and rapid immune-mediated clearance of senescent cells, is widely implicated in processes involving physiological tissue remodelling, including during embryo development, placenta formation, and wound healing (Muñoz-Espín and Serrano, 2014; Van, 2014). By contrast, persisting senescent cells cause chronic inflammation or ‘inflammaging’ (Birch and Gil, 2020), a pathological state that underpins ageing and age-related disorders. We demonstrated that inflammatory reprogramming of EnSC burdened by replication stress leads to the emergence of acute senescent cells during the implantation window (Brighton et al., 2017; Lucas et al., 2020; Kong et al., 2021). Upon successful implantation and continuous progesterone signalling, decidual cells co-opt uNK cells to eliminate their senescent counterparts through granule exocytosis (Brighton et al., 2017; Lucas et al., 2020; Kong et al., 2021). Clearance of senescent decidual cells likely necessitates recruitment of bone marrow-derived decidual precursor cells, which confer tissue plasticity for rapid decidual expansion in early pregnancy (Diniz-da-Costa et al., 2021). Importantly, lack of clonogenic decidual precursor cells and a pro-senescent decidual response are linked to recurrent pregnancy loss (Lucas et al., 2016; Lucas et al., 2020; Tewary et al., 2020).

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.

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.

Single-cell analysis of differentiating endometrial assembloids indicates that the sequence of events leading up to the implantation window, and beyond, requires divergence of both glandular EpC and EnSC into differentiated and senescent subpopulations, a process likely determined by the level of replication stress incurred by individual cells in the preceding proliferative phase (Brighton et al., 2017). Importantly, we demonstrate that acute senescence in glandular EpC (EpS5) underpins production of an implantation-specific SASP, comprising canonical implantation factors and growth factors, such as amphiregulin (AREG) and epiregulin (EREG), implicated in transforming cytotrophoblasts into extravillous trophoblasts (Cui et al., 2020; Yu et al., 2019). On the other hand, the transcriptome profile of differentiated EpC (EpS4) revealed a pivotal role for this subpopulation in prostaglandin and glycodelin synthesis. Prostaglandins, and specifically PGE2, are indispensable for implantation (Ruan et al., 2012), whereas glycodelin is an abundantly secreted, multifaceted glycoprotein involved in blastocyst attachment, trophoblast differentiation, and immune modulation in early pregnancy (Lee et al., 2016). Further, differentiated EpC highly express SLC2A1, encoding the major glucose transporter GLUT1. Glucose is required for glycogen synthesis, an essential component of glandular secretions that nourishes the conceptus prior to the onset of placental perfusion around 10 weeks of pregnancy (Burton et al., 2020). The fate and function of senescent EpC in pregnancy are unknown. Arguably, localized secretion of proteinases by senescent EpC may promote breakdown of the surrounding basement membrane, thereby facilitating endoglandular trophoblast invasion and access to histotrophic nutrition in early gestation (Huppertz, 2019; Moser et al., 2010). In non-conception cycles, the abundance of p16^INK4-positive glandular EpC rises markedly during the late-luteal phase (Brighton et al., 2017), indicating that senescent EpC are progesterone-independent and likely responsible for glandular breakdown in the superficial endometrial layer at menstruation.

Decidual transformation of EnSC in assembloids unfolded largely as anticipated from previous studies, that is, starting with an acute pre-decidual stress response and leading to the emergence of both decidual and senescent decidual subpopulations (Brighton et al., 2017; Lucas et al., 2020; Kong et al., 2021). Like their epithelial counterparts, senescent decidual cells have a conspicuous secretory phenotype. We identified 56 and 72 genes encoding secreted factors upregulated in senescent epithelial and decidual subpopulations, respectively. However, only 15 genes were shared, indicating that the SASP generated in both cellular compartments is distinct. As glandular secretions drain into the uterine cavity, the embryonic microenvironment is therefore predicted to change abruptly upon breaching of the luminal epithelium. Recent comparative metabolomics of apical and basolateral endometrial gland-like organoid secretomes also supports the prediction of an asymmetrical profile of glandular secretions in the pre- and post-implantation microenvironments (Simintiras et al., 2021).

Based on computational predictions of ligand-receptor interactions, we demonstrated that the decidual response in assembloids can be targeted pharmacologically with only modest impact on glandular function and, by extension, the preimplantation embryo milieu. Specifically, dasatinib, a tyrosine kinase inhibitor, was highly effective in blunting the pre-decidual stress response, leading to a dramatic expansion of anti-inflammatory decidual cells and near-total elimination of senescent decidual cells. Dasatinib also inhibited the emergence of TP and shifted the transcriptional profile of the remaining transitional cells towards a decidual phenotype. An analogous population of ambiguous cells expressing both epithelial and mesenchymal marker genes was recently identified in midluteal endometrium by scRNA-seq analysis (Lucas et al., 2020). Further, based on CellPhoneDB and GO analyses, transitional cells are predicted to be highly autonomous and involved in tissue regeneration, in line with experimental evidence that MET drives re-epithelization of the endometrium following menstruation and parturition (Owusu-Akyaw et al., 2019; Patterson et al., 2013). Thus, the level of endogenous cellular stress generated by the endometrium during the window of implantation calibrates the subsequent decidual trajectory, either promoting the formation of a robust decidual matrix or facilitating tissue breakdown and repair. Further, an in-built feature of both trajectories is self-enforcement as decidual cells recruit and activate uNK cells to eliminate their senescent counterparts (Brighton et al., 2017; Lucas et al., 2020; Kong et al., 2021), whereas senescent decidual cells induce secondary senescence in neighbouring decidual (Brighton et al., 2017; Ozaki et al., 2017) and, plausibly, uNK cells (Rajagopalan and Long, 2012).

Clinically, recurrent pregnancy loss, defined as multiple miscarriages, is associated with loss of endometrial clonogenicity (Lucas et al., 2016; Diniz-da-Costa et al., 2021), uNK cell deficiency and excessive decidual senescence (Lucas et al., 2020; Tewary et al., 2020), and rapid conceptions (also referred to as ‘superfertility’) (Dimitriadis et al., 2020; Ticconi et al., 2020). Conversely, lack of a proliferative gene signature in midluteal endometrium and premature expression of decidual PRL have been linked to recurrent implantation failure (Berkhout et al., 2020b; Koler et al., 2009; Koot et al., 2016), a pathological condition defined by a failure to achieve a pregnancy following transfer of one or more high-quality embryos in multiple IVF cycles (Polanski et al., 2014). We reasoned that these aberrant implantation environments can be recapitulated in assembloids by manipulating the level of decidual senescence. In line with these predictions, the presence of senescent decidual cells created a permissive environment in which migratory decidual cells interacted with expanding blastocysts, although continuous SASP production also promoted breakdown of the assembloids. Conversely, in the absence of senescent decidual cells, non-expanding embryos became entrapped in a robust but stagnant decidual matrix. These observations are in keeping with previous studies demonstrating that implantation of human embryos depends critically on the invasive and migratory capacities of decidual cells (Berkhout et al., 2020a; Gellersen et al., 2010; Grewal et al., 2008; Weimar et al., 2012). Our co-culture experiments also highlighted the shortcomings of assembloids as an implantation model, including the lack of a surface epithelium to create distinct pre- and post-implantation microenvironments and the absence of key cellular constituents, such as innate immune cells.

In summary, parsing the mechanisms that control implantation has been hampered by the overwhelming complexity of factors involved in endometrial receptivity. Our single-cell analysis of decidualizing assembloids suggests that this complexity reflects the reliance of the human endometrium on rapid E2-dependent proliferation and replicative exhaustion to generate both differentiated and senescent epithelial and stromal subpopulations in response to the postovulatory rise in progesterone. We demonstrate that senescent cells in both cellular compartments produce distinct bioactive secretomes, which plausibly prime pre-implantation embryos for interaction with the luminal epithelium and then stimulate encapsulation by underlying decidual stromal cells. Based on our co-culture observations, we predict that a blunted pre-decidual stress response causes implantation failure because of a lack of senescence-induced tissue remodelling and accelerated decidualization. Conversely, a heightened stress response leading to excessive decidual senescence may render embryo implantation effortless, albeit in a decidual matrix destined for breakdown and repair. Finally, we demonstrated that pre-decidual stress responses can be modulated pharmacologically, highlighting the potential of endometrial assembloids as a versatile system to evaluate new or repurposed drugs aimed at preventing reproductive failure.

Single cell RNAseq data presented in this paper are openly available as a Gene Expression Omnibus DataSet (https://www.ncbi.nlm.nih.gov/gds) under accession number GSE168405. Other source data are presented in the Source Data tables as indicated in the corresponding Figure legends.

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Author details

1. Thomas M Rawlings

   1. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
   2. Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom

   Contribution

   Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

2. Komal Makwana

   1. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
   2. Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom

   Contribution

   Formal analysis, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

3. Deborah M Taylor

   1. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
   2. Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom
   3. Centre for Reproductive Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom

   Contribution

   Conceptualization, Writing – review and editing

   Competing interests

   No competing interests declared

4. Matteo A Molè

   Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

5. Katherine J Fishwick

   Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

6. Maria Tryfonos

   1. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
   2. Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

7. Joshua Odendaal

   1. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
   2. Tommy’s National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, United Kingdom

   Contribution

   Conceptualization, Writing – review and editing

   Competing interests

   No competing interests declared

8. Amelia Hawkes

   1. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
   2. Tommy’s National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, United Kingdom

   Contribution

   Conceptualization, Writing – review and editing

   Competing interests

   No competing interests declared

9. Magdalena Zernicka-Goetz

   1. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
   2. Synthetic Mouse and Human Embryology Group, California Institute of Technology (Caltech), Division of Biology and Biological Engineering, Pasadena, United Kingdom

   Contribution

   Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7004-2471

10. Geraldine M Hartshorne

    1. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
    2. Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom
    3. Centre for Reproductive Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom

    Contribution

    Conceptualization, Writing – review and editing

    Competing interests

    No competing interests declared

11. Jan J Brosens

    1. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
    2. Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom
    3. Tommy’s National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, United Kingdom

    Contribution

    Resources, Formal analysis, Supervision, Project administration, Conceptualization, Funding acquisition, Visualization, Writing – original draft, Writing – review and editing

    For correspondence

    J.J.Brosens@warwick.ac.uk

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-0116-9329

12. Emma S Lucas

    1. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
    2. Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom

    Contribution

    Formal analysis, Investigation, Methodology, Project administration, Funding acquisition, Visualization, Writing – original draft, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8571-8921

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