Pinopodes: Recent advancements, current perspectives, and future directions

Abstract

Successful embryo implantation is a complex and highly regulated process involving precise synchronization between the fetal-derived trophoblast cells and maternal uterine luminal epithelium. Multiple endocrine-driven factors are important for controlling the timely receptivity of the uterus, and this complexity underscores implantation failure as a major cause of recurrent infertility associated with assisted reproductive technologies. One particular cellular structure often hypothesized to promote receptivity is the pinopode or uterodome - a hormonally regulated, large cellular protrusion on the uterine epithelial surface. Recent clinical studies associate pinopodes with favorable fertility outcomes in women, and because they are directly linked to an increase in progesterone levels, the potential utility of these hormone-regulated cell biological structures in predicting or improving implantation in a clinical setting holds promise. In this review, we aim to generate interest in pinopodes from the broader cell biology and endocrinology communities, re-examine methodologies in pinopode research, and identify priorities for future investigation of pinopode structure and function in women's reproductive health.

Keywords: Endometrial receptivity; Implantation; Pinopodes; Progesterone; Uterodomes.

Fig. 1.

A) Pinopodes are large plasma membrane protrusions of uterine epithelial cells that transiently project toward the uterine lumen during the “window of implantation.” B) Scanning electron micrograph of the murine uterine epithelial surface at pseudopregnancy day 3.5, the peak timing of the “window of implantation.”

Fig. 2.

A) Representative scanning electron microscopy pinopode images from women experiencing infertility issues. Each image represents a different patient and demonstrates the variety of pinopodes in a given sample. Arrows denote regressing pinopode and cilia. Endometrial biopsies were collected between LH +6 to +10 in a natural menstrual cycle. Figure used from Aunapuu et al., 2018 (CC BY 4.0) under the creative commons attribution license. B) Representative stages of pinopode and microvilli development during pseudopregnancy (pp) in the mouse endometrium. On day 2.5 of pseudopregnancy, pinopodes appear to expand and have punctate holes. By day 3.5 of pseudopregnancy, pinopodes rise above microvilli and become smooth and spherical in shape. Few microvilli are present on day 4.5 of pseudopregnancy with pinopodes demonstrating more of a deflated and elongated appearance. Scale bars, 2 μm.

Fig. 3.

Scanning electron microscopy of the mouse endometrium on day 4.5 of pseudopregnancy. Some pinopodes (arrows) appear to rupture and release vesicular contents. Scale bars, 1 μm.