Equine cervical remodeling during placentitis and the prepartum period: a transcriptomic approach

in Reproduction
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  • 1 Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, Kentucky, USA
  • 2 Theriogenology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
  • 3 UK Veterinary Diagnostic Laboratory, University of Kentucky, Kentucky, USA
  • 4 Department of Clinical Sciences, Auburn University College of Veterinary Medicine, Auburn, Alabama, USA
  • 5 Department of Animal Reproduction, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
  • 6 Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California, USA
  • 7 Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, Tennessee, USA

Correspondence should be addressed to B A Ball; Email: b.a.ball@uky.edu
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Cervical remodeling is a critical component in both term and preterm labor in eutherian mammals. However, the molecular mechanisms underlying cervical remodeling remain poorly understood in the mare. The current study compared the transcriptome of the equine cervix (cervical mucosa (CM) and stroma (CS)) during placentitis (placentitis group, n  = 5) and normal prepartum mares (prepartum group, n  = 3) to normal pregnant mares (control group, n  = 4). Transcriptome analysis identified differentially expressed genes (DEGs) during placentitis (5310 in CM and 907 in CS) and during the normal prepartum period (189 in CM and 78 in CS). Our study revealed that cervical remodeling during placentitis was dominated by inflammatory signaling as reflected by the overrepresented toll-like receptor signaling, interleukin signaling, T cell activation, and B cell activation pathways. These pathways were accompanied by upregulation of several proteases, including matrix metalloproteinases (MMP1, MMP2, and MMP9), cathepsins (CTSB, CTSC, and CTSD) and a disintegrin and metalloproteinase with thrombospondin type 1 motifs (ADAMTS1, ADAMTS4, and ADAMTS5), which are crucial for degradation of cervical collagens during remodeling. Cervical remodeling during placentitis was also associated with upregulation of water channel-related transcripts (AQP9 and RLN), angiogenesis-related transcripts (NOS3, ENG1, THBS1, and RAC2), and aggrecan (ACAN), a hydrophilic glucosaminoglycan, with subsequent cervical hydration. The normal prepartum cervix was associated with upregulation of ADAMTS1, ADAMTS4, NOS3 and THBS1, which might reflect an early stage of cervical remodeling taking place in preparation for labor. In conclusion, our findings revealed the possible key regulators and mechanisms underlying equine cervical remodeling during placentitis and the normal prepartum period.

Supplementary Materials

    • Supplementary Figure 1. Summary of the bioinformatics and functional genomics pipeline used in the current study.
    • Supplementary Figure 2. Histopathological evaluation of equine cervical tissue. A) Representative H&E photomicrographs of equine cervical tissue retrieved from control, placentitis and normal prepartum mares. B) Representative photomicrographs of the equine cervix stained with Gram stain. The cervical tissue retrieved from a mare with induced placentitis showed numerous gram-positive cocci. Findings such as this are suggestive of cervical tissue infection with Streptococcus equi subsp. zooepidemicus.
    • Supplementary Figure 3. Heat map of the differentially expressed genes (DEGs; FDR <0.05) that were exclusively expressed in cervical mucosa (A) and stroma (B) during placentitis in comparison to control group. The heat map was created using the normalized FPKMs of the DEGs (log10 (FPKM of the DEG +1)). The icons at the bottom indicate the sample group (green circle = control, and red triangle =placentitis). The heat map was generated using the R package “gplots v3.0.4”.
    • Supplementary Figure 4. Overrepresented protein class in cervical mucosa (A-1) and stroma (A-2) during placentitis. Overrepresented protein class in cervical mucosa (B-1) and stroma (B-2) during prepartum period.
    • Supplementary Figure 5. Overrepresented pathways in cervical mucosa during prepartum period. Panther pathway analysis was used to identify the overrepresented pathways from the DEGs in cervical mucosa during prepartum period. The bars represent the number of genes in each overrepresented pathway, while the dotted line represents –Log10 (Adj P-value).
    • Supplementary Figure 6. The interaction between upstream regulators identified in placentitis dataset in cervical mucosa (A) and stroma (B). The network was generated by matching the identified upstream regulators to all known protein-protein interactions networks using STRING version 10.3 and visualized by Cytoscape 2.8.6. Red circles represent upregulated genes, while green circles represent downregulated genes.
    • Supplementary Table 1. Read counts and mapping quality of Illumina RNA-sequencing dataset from equine cervix (cervical mucosa; CM and cervical stroma; CS) retrieved from control, placentitis and prepartum groups.
    • Supplementary Table 2. Differentially expressed genes (DEGs) in equine cervix (cervical mucosa; CM and cervical stroma; CS) in placentitis and prepartum groups in comparison to control group.
    • Supplementary Table 3. Upstream regulators in equine cervix (cervical mucosa; CM and cervical stroma; CS) during placentitis and prepartum as identified by upstream regulator analysis performed on Ingenuity Pathway Analysis (IPA).

 

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