Preterm birth is the leading cause of infant mortality worldwide and is associated with an increased risk of long-term cognitive impairment. Maternal infection is a known cause of preterm birth; however, our understanding of susceptibility factors that predispose some women to infection-associated preterm birth remains unclear. Yucel Akgul and colleagues at the University of Texas Southwestern Medical Center determined that the glycosaminoglycan hyaluronan is a key factor in the extracellular matrix that is necessary for normal epithelial cell differentiation and barrier function of the lower reproductive tract. In a murine model, the absence of hyaluronan specifically in the epithelial matrix predisposed mice to preterm birth when faced with an ascending bacterial infection. Hyaluronan has long been proposed to drive disorganization and hydration of the cervical stromal extracellular matrix to allow the cervix to open during the birth process, yet unexpectedly the absence of stromal hyaluronan had no effect on delivery in the absence of infection. Together, these findings provide important insights into mechanisms by which the extracellular matrix can influence cellular function, in particular the regulation of mucosal epithelial biology and reveal a potential risk factor for preterm birth. The accompanying image of Mason’s Trichrome stained ectocervical sections from pregnant WT (left) and hyaluronan-deficient (left) animals demonstrates the aberrant organization and differentiation of cervical epithelia in animals lacking hyaluronan.
Increased synthesis of cervical hyaluronan (HA) from early to late pregnancy has long been proposed to play an essential role in disorganization of the collagen-rich extracellular matrix to allow for maximal compliance and dilation of the cervix during the birth process. Here, we show that HA is not essential for increased cervical distensibility during late pregnancy. Rather, cervicovaginal HA plays an unanticipated important role in epithelial barrier protection of the lower reproductive tract. Specifically, HA depletion in the cervix and vagina resulted in inappropriate differentiation of epithelial cells, increased epithelial and mucosal permeability, and strikingly increased preterm birth rates in a mouse model of ascending vaginal infection. Collectively, these findings revealed that although HA is not obligatory for cervical compliance, it is crucial for maintaining an epithelial and mucosal barrier to limit pathogen infiltration of the lower reproductive tract during pregnancy and thereby is protective against infection-mediated preterm birth.
Yucel Akgul, R. Ann Word, Laura M. Ensign, Yu Yamaguchi, John Lydon, Justin Hanes, Mala Mahendroo