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.
Highlights
The human endometrium is defined by its ability to execute opposing functions, often simultaneously, and to transition seamlessly between different physiological states
Single-cell “omics” approaches are rapidly transforming our understanding of the cellular dynamics underpinning key endometrial functions, including embryo implantation, menstrual shedding and repair, and the spectacular transformation of a short-lived uterine mucosa into a robust matrix that accommodates the placenta throughout pregnancy
A recent study demonstrated that bone marrow transplants from wild-type mice to mice carrying a heterozygous deletion of Hoxa11, a pivotal decidual transcription factor, restore the decidual response and prevent pregnancy loss in these animals [16]
Summary
The human endometrium is defined by its ability to execute opposing functions, often simultaneously, and to transition seamlessly between different physiological states. The discovery that endometrial regeneration and tissue homeostasis are critically dependent on bone marrow-derived, non-hematopoietic progenitor cells and innate immune cells has all but torpedoed this historical misconception [13,14,15,16,17]. Novel technologies, such as single-cell RNA-sequencing and endometrial organoid models, are revealing how oestrogen (E2)-dependent proliferation during the follicular phase controls the specification of endometrial epithelial and stromal cells into different subpopulations with distinct functions following ovulation [8, 18, 19]. We highlight the importance of dyshomeostasis of decidual subpopulations in recurrent miscarriage and touch upon the ensuing therapeutic opportunities
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