Molecular markers of preterm labor in the choriodecidua

Abstract

Because relevant biochemical changes are known to begin at the choriodecidual interface some weeks before actual clinical onset of labor, we hypothesized that the preterm choriodecidua may display gene and protein expression patterns specific to preterm labor. Transcriptomic (microarray) and proteomic (2-dimensional gel electrophoresis [2DGE]) profiling methodologies were used to compare changes in choriodecidual tissue collected from women who delivered before 35 weeks of gestation following spontaneous preterm labor (n = 12) and gestation-matched nonlaboring controls (n = 7). Additionally, 2DGE was used to compare differences in protein expression during term and preterm labor and to construct a choriodecidual proteome map. Overall, expressed transcripts and proteins indicated active tissue remodeling independent of labor status and an association with inflammatory processes during labor. Spontaneous, infection-induced and abruption-associated preterm deliveries were each defined by distinct transcriptional profiles. Proteins osteoglycin and progesterone receptor component 2 (PGRMC2) were upregulated during term and preterm labor while galectin 1, annexin 3, annexin 5, and protein disulfide isomerase (PDI) were upregulated only during preterm labor, suggesting a probable association with the underlying pathology. Together, these results represent novel data that warrant further investigations to elucidate plausible causal relationships of these molecules with spontaneous preterm delivery.

Figure 1. Cluster analysis of preterm samples

Clustering based on overall gene expression highlighted the heterogeneous nature of the samples that were grouped according to clinical and histological data. In general, the PTNIL control group displayed the greatest heterogeneity. The pure (PPL), infection (IPL) and abruption (APL) subgroups were relatively more homogeneous. While it seemed that the PTNIL samples with placenta praevia (3&4) and abruption (6) might correlate better to the APL samples, sample 5 correlated better with PPL and sample 6 with IPL samples. Four of the IPL samples clustered together. Samples 16 and 17, collected from women with a vaginal infection but no evidence of histological chorioamnionitis displayed the closest similarity. Abbreviations: PTNIL = Preterm not-in-labor, PPL = Pure Preterm in-labor, IPL = Infection Preterm in-labor, APL = Abruption Preterm in-labor

Figure 2. Venn diagram depicting significant canonical signalling pathways associated with the mapped transcripts from the laboring preterm subgroups

PTIL = Preterm in-labor group

Figure 3. Cellular location & functional categorization of identified proteins

(A) Cellular Location: The majority of the identified proteins were revealed to be cytosolic and with subcellular proteins limited to about 20%. (B) Functional Classification: Based on the biological process associated with their function, the proteins could be grouped into six main classes. Those associated with protein and energy metabolism predominate while other major classes included cell communication/signal transduction, cell growth/maintenance and transport. The location and molecular function of each protein is listed in Supplementary Table 5.

Figure 4

Molecular relationships of the differentially expressed proteins indicate an association with TNF-α signaling. In grey are proteins that were significantly overexpressed during preterm labor. Broken lines represent indirect relationships while unbroken lines indicate direct relationships between two proteins.