Cervical hyaluronan biology in pregnancy, parturition and preterm birth

Abstract

Cervical hyaluronan (HA) synthesis is robustly induced in late pregnancy in numerous species including women and mice. Recent evidence highlights the diverse and dynamic functions of HA in cervical biology that stem from its expression in the cervical stroma, epithelia and immune cells, changes in HA molecular weight and cell specific expression of HA binding partners. Mice deficient in HA in the lower reproductive tract confirm a structural role of HA to increase spacing and disorganization of fibrillar collagen, though this function is not critical for pregnancy and parturition. In addition, cervical HA depletion via targeted deletion of HA synthase genes, disrupts cell signaling required for the differentiation of epithelia and their mucosal and junctional barrier, resulting in increased susceptibility to ascending infection-mediated preterm birth. Finally the generation of HA disaccharides by bacterial hyaluronidases as made by Group B streptococcus can ligate toll like receptors TLR2/4 thus preventing appropriate inflammatory responses as needed to fight ascending infection and preterm birth. This review summarizes our current understanding of HA's novel and unique roles in cervical remodeling in the process of birth.

Keywords: Ascending infection; Cervical ripening; Cervix; Hyaluronan; Parturition; Preterm birth.

Figure 1

Top Panel Schematic to illustrate disruption in cervical epithelial cell differentiation in the absence of HA. As a result there is a breach of both the mucosal barrier and the cell junctional barriers resulting in the ability of pathogens to move into the cervix as well as ascend into the upper reproductive tract. Lower panel. Loss of the Has2 gene and not Has1 and Has3 in the cervix results in an increased susceptibility to ascending E. coli induced preterm birth rates. Blue bars indicate PTB rates when 10⁷ CFUs of E. coli are placed in the vagina on gestation day 16 and purple bars indicate PTB rates when 10⁵ CFUs are placed in the vagina on gestation day 16. PTB is birth is defined as delivery that occurs within 48 hours of E. coli exposure. WT-wild type, Has2-Has2^fl/flPR^Cre+, Has1/3-Has1^−/−Has3^−/− and Has1/2/3-Has1^−/−, Has2^fl/flPR^Cre+, Has3^−/−.

Figure 2

Potential mechanism by which Group B streptococcus elicits hyaluronidase-mediated breakdown of epithelial HA to evade immune-detection. (Left panel) High molecular weight HA does not bind TLR receptors thus in the presence of high molecular weight HA pathogen derived TLR ligands (eg peptidoglycans, lipopolysaccharide) can bind TLR2 or TLR4 respectively to activate signaling cascades in the cervical epithelia and/or recruited immune cells that can deploy a proinflammatory immune response to fight ascending infection. (Right panel) Pathogens such as Group B streptococcus (GBS)) secrete hyaluronidase that breakdown HA to disaccharides which ligate TLR2 or TLR4 thus prevent binding of pathogen derived TLR ligands that elicit proinflammatory responses as required to prevent ascending infection and preterm birth.