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.

ESHRE good practice recommendations on recurrent implantation failure

“…Moreover, increasing evidence is emerging for the role of decidualized endometrium acting as a gatekeeper to implantation after the epithelial layer is breached. Novel markers of this function are being developed ( Muter et al , 2021 ).…”

In Memory of Ivo Brosens: Reflections on the Pathophysiology of Neonatal Uterine Bleeding

“…The capacity for rapid proliferation and tissue growth set the nonpregnant endometrium of menstruating species apart from that of other species [61]. Decidualization of differentiating stromal cells can be triggered by stress [62], and it is not possible to rule this out as a factor in cases examined histologically following fetal demise. During their life cycle, stromal cells adopt different cellular states: some, but not all, are compatible with a decidual response.…”

“…Differentiation of decidual stromal cells is induced by progesterone and the cyclic AMP/protein kinase A (cAMP/PKA) pathway [63]. It was proposed that prostaglandin E 2 (PGE2) is likely to be the signal that, in conjunction with progesterone, ancestrally induced decidualization [62].…”

Spatial targeting of the prostaglandin receptor EP2 to very early endosomes co-ordinates PGE2-mediated cAMP signaling in decidualizing human endometrium

“…The human endometrium undergoes profound and dynamic remodeling across the menstrual cycle, with changes marked by cyclical phases of menstrual repair, estrogen-dependent proliferation, progesterone-dependent differentiation and senescence-like tissue break-down and shedding. 1,2 In particular, the process of decidualization, denoting the differentiation of endometrial stromal fibroblasts into specialized secretory decidual cells, occurs during the secretory phase of the menstrual cycle after ovulation, concomitant with the secretory transformation of endometrial glands, vascular remodeling, and immune cell recruitment. The process creates a supportive and nutritive environment that is indispensable for embryo implantation, placentation and pregnancy.…”