Transcriptome and proteome dynamics of cervical remodeling in the mouse during pregnancy

Abstract

During gestation, the female reproductive tract must maintain pregnancy while concurrently preparing for parturition. Here, we explore the transitions in gene expression and protein turnover (fractional synthesis rates [FSR]) by which the cervix implements a transition from rigid to compliant. Shifts in gene transcription to achieve immune tolerance and alter epithelial cell programs begin in early pregnancy. Subsequently, in mid-to-late pregnancy transcriptional programs emerge that promote structural reorganization of the extracellular matrix (ECM). Stable isotope labeling revealed a striking slowdown of overall FSRs across the proteome on gestation day 6 that reverses in mid-to-late pregnancy. An exception was soluble fibrillar collagens and proteins of collagen assembly, which exhibit high turnover in non-pregnant cervix compared to other tissues and FSRs that continue throughout pregnancy. This finding provides a mechanism to explain how cross-linked collagen is replaced by newly synthesized, less-cross-linked collagens, which allows increased tissue compliance during parturition. The rapid transition requires a reservoir of newly synthesized, less cross-linked collagens, which is assured by the high FSR of soluble collagens in the cervix. These findings suggest a previously unrecognized form of “metabolic flexibility” for ECM in the cervix that underlies rapid transformation in compliance to allow parturition.

Dynamic states of cervical epithelia during pregnancy and epithelial barrier disruption

“…Previous bulk transcriptomic and proteomic studies suggest a marked change in epithelial cell phenotype and function during early cervical softening relative to NP (Nallasamy et al, 2021). To define the epithelial subtypes and cell state transitions induced in the early softening period, we compared epithelial subtypes in NP and GD6.…”

Molecular Landscape of Pelvic Organ Prolapse Provides Insights into Disease Etiology

“…The POP landscape reveals four main biological processes that operate in epithelial cells, fibroblasts, and the surrounding ECM of the female urogenital tract: EMT, immune response activation, ECM modulation, and fibroblast survival and apoptosis. During pregnancy and (vaginal) delivery, similar changes in immune response activation and ECM modulation than in the POP landscape occur [ 20 , 21 ], which is interesting as increased parity and vaginal delivery are established environmental risk factors for developing POP [ 5 ].…”

Spontaneous preterm birth: Involvement of multiple feto-maternal tissues and organ systems, differing mechanisms, and pathways

“…Dynamic changes in ECM proteins, mainly collagen, decorin, elastin, glycosaminoglycans, and hyaluronic acid, occur in cervical remodeling in labor ( 302 , 321 – 324 ). Proteomic studies have shown that highly cross-linked collagens were replaced by newer, less cross-linked collagen during parturition ( 324 ), resulting in increased tissue compliance in cervical ripening. Aside from collagen, hyaluronic acid is essential due to its role as a component of the ECM.…”