The Role of Decidual Subpopulations in Implantation, Menstruation and Miscarriage

Abstract

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.

Keywords: decidualization; endometrium; implantation; innate immunity; menstruation; miscarriage; senescence.

Figure 1

Dynamic changes in cell states across the menstrual cycle. (A) Following menstruation, rapid re-epithelization of the endometrium may involve mesenchymal-epithelial transition (MET), proliferation of epithelial progenitors from unshed areas, or both. Positional oestrogen-dependent proliferation, reflecting an IFN-γ gradient generated by lymphoid aggregates residing in the endometrial-myometrial junction, imposes various levels of replication stress on individual cells during the follicular phase, which in turn drives the divergence in cell states upon decidualization. (B) Upper panel: In a non-conception cycle, falling progesterone levels promote senDeC/transDeC dominance and bystander senescence via prolonged SASP secretion, resulting in leukocyte recruitment and menstrual breakdown. Lower panel: Upon successful embryo implantation, progesterone-dependent DeC cells control rapid clearance of senDeC by recruiting and activating uNK cells.

Figure 2

Embryo biosensing and selection. (A) Sufficient hCG secretion from implanting blastocysts is required to prevent corpus luteum involution. (B) High-fitness human blastocysts elicit a supportive decidual response, including secretion of evolutionary conserved serine proteases that activate epithelial Na⁺ channel (ENaC) expressed on luminal epithelial cells, triggering Ca²⁺ signalling, ER expansion and subsequent induction of implantation specific genes. Further, by secretion of microRNA miR-320a, competent blastocysts promote migration of pre-decidualizing cells. Conversely, low fitness embryos trigger a decidual ER stress response, repression of key implantation factors, and secretion of CXCL12 and CXCL8 leading to neutrophil recruitment and activation. (C) HYAL2 production in developmentally competent blastocysts cleaves HMWHA into LMWHA, which supports further development. Loss or reduction of HYAL2 in low-fitness embryos promotes HMWHA accumulation, which binds to CD44 expressed on uNK cells and disables selective killing of senDeC.

Figure 3

Expression of cell fate biomarkers. (A) In silico analysis of GDS2052 microarray data showing transcript expression of the DeC biomarker SCARA5 and the senDeC biomarker DIO2 in proliferative, early-, mid- and late-secretory endometrium expressed in arbitrary units. (B) Temporal expression of SCARA5 and DIO2 transcripts in human endometrium from single cell profiling of endometrial biopsies obtained across the cycle (n = 15). Data were extracted from Garcia-Alonso et al. (148) and available on reproductivecellatlas.org.