Compartment-specific transcriptional programs of the gravid human myometrium underlie labor and uterine atony
The study provides insights into the complex biology of the myometrium during pregnancy and labor, highlighting the role of specific signaling pathways in uterine atony. It suggests that uterine atony may involve structural predispositions rather than just signaling failures.
Where it sits
this study against the rest of the oxytocin corpusSummary and findings
This study investigates the transcriptional programs of the human myometrium during pregnancy, focusing on smooth muscle and endothelial cell subtypes. It analyzes samples from 15 patients collected during cesarean delivery, revealing insights into uterine function and complications like uterine atony. The findings highlight the role of FSH signaling and changes in actin architecture in the context of labor and postpartum hemorrhage.
Abstract
<title>Abstract</title> <p> Background The human myometrium undergoes an extraordinary physiological transformation during pregnancy to accommodate the growing fetus and facilitate delivery. Recent single cell RNA sequencing (scRNA-seq) studies mapping the uterine landscape, are technically limited due to underrepresentation of the large, hypertrophied uterine smooth muscle cells (uSMC) essential to pregnancy and parturition. Our high-resolution single nucleus and spatial transcriptomic atlas overcomes these constraints and provides mechanistic insights into uterine function and life-threatening complications such as uterine atony, the leading cause of postpartum hemorrhage (PPH) and global maternal mortality. Methods The present report includes comprehensive single-nucleus RNA sequencing (snRNA-seq) data of the human gravid myometrium collected during cesarean delivery from term and preterm, laboring and nonlaboring pregnant patients. Spatial validation of cell-type identities was accomplished with MERFISH and RNAscope. These data were interrogated to define: (1) pregnancy-specific smooth muscle cell signaling; (2) transcriptomic progression during labor; and (3) the molecular underpinnings of PPH due to uterine atony. Findings were validated at the RNA, protein, and functional levels in uSMC at low passage primary culture. Results Myometrial samples collected from 15 patients resolved the complex myometrial landscape into two distinct smooth muscle cell and four endothelial cell subtypes. Pregnancy induced follicle stimulating hormone receptor expression ( <italic>FSHR)</italic> in uSMC with definitive, functional FSH-FSHR signaling present in uSMC from the pregnant myometrium. With labor, we identified cell-type specific hypoxia signaling and metabolic reprogramming among the fibrovascular niche. We additionally discovered that patients with uterine atony upregulate expression of <italic>ENAH</italic> compared to those with preserved uterine contractility. ENAH is an actin-regulatory protein which orchestrates cytoskeletal dynamics; the physiologic significance of increased ENAH expression is illustrated by a distinct, stellate F-actin architecture in atony uSMC, consistent with diversion of actin into peripheral protrusions at the expense of the organized contractile apparatus required for sustained postpartum contractility. Conclusions This snRNA-seq atlas provides a foundational framework for investigation into human myometrial biology. Crucially, it characterizes previously underrepresented uterine smooth muscle cells which define the smooth muscle and endothelial cell subtypes, alongside dynamic metabolic changes in the fibrovascular niche during labor. Our work shifts the understanding of PPH from a simple failure of oxytocin signaling to, in some cases, a pre-defined mechanical state. By uncovering a pre-existing structural predisposition to uterine atony and a functional <italic>FSHR</italic> axis in the myometrium, this work suggests new avenues for prediction and treatment of PPH. </p>
Background
This research addresses the physiological changes in the human myometrium during pregnancy and labor, which are critical for successful delivery. Prior studies have highlighted the importance of uterine smooth muscle cells, but their specific roles have been underrepresented. Understanding these mechanisms is vital for addressing complications such as uterine atony, a leading cause of postpartum hemorrhage.
Methods
The study utilized single-nucleus RNA sequencing (snRNA-seq) to analyze myometrial samples collected during cesarean delivery from term and preterm, laboring and nonlaboring pregnant patients. The population consisted of 15 patients, and the study aimed to characterize cell-type specific signaling and transcriptomic changes during labor.
Results
The primary endpoint revealed that myometrial samples from 15 patients identified two distinct smooth muscle cell subtypes and four endothelial cell subtypes. The study noted that patients with uterine atony exhibited increased expression of ENAH compared to those with preserved contractility.
Interpretation
These findings contribute to the understanding of uterine biology and the mechanisms underlying uterine atony. While the study identifies significant changes in gene expression, the clinical relevance of these findings remains uncertain due to the small sample size and lack of direct treatment outcomes. The results suggest a shift in understanding uterine atony beyond oxytocin signaling to include structural predispositions.
Key findings
- Myometrial samples from 15 patients resolved into two distinct smooth muscle cell and four endothelial cell subtypes.
- Pregnancy induced FSHR expression in uSMC with definitive FSH-FSHR signaling present.
- Patients with uterine atony upregulated ENAH expression compared to those with preserved uterine contractility.
Limitations
- small sample size of 15 patients
- does not provide direct clinical outcomes
- focuses on gene expression without treatment implications