Hyaluronan in cervical epithelia protects against infection-mediated preterm birth
Yucel Akgul, … , Justin Hanes, Mala Mahendroo
Yucel Akgul, … , Justin Hanes, Mala Mahendroo
Published November 10, 2014
Citation Information: J Clin Invest. 2014;124(12):5481-5489. https://doi.org/10.1172/JCI78765.
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Research Article Reproductive biology

Hyaluronan in cervical epithelia protects against infection-mediated preterm birth

Abstract

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.

Authors

Yucel Akgul, R. Ann Word, Laura M. Ensign, Yu Yamaguchi, John Lydon, Justin Hanes, Mala Mahendroo

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Figure 1

The majority of cervical HA is synthesized by Has2, with ≥93% depletion in Has2 KO and Has1/2/3 KO mice.

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The majority of cervical HA is synthesized by Has2, with ≥93% depletion ...
(A) HA and CS/DS GAGs (sGAG) were quantified by FACE in d18 cervices from WT, Has2 KO, Has1/3 KO, and Has1/2/3 KO mice. n = 3 per genotype. (B) Decreased Has2 expression in Has2 KO and Has1/2/3 KO cervix. Has1 and Has3, while expressed at low levels in the cervix, did not increase to compensate for Has2 loss. n = 4 per genotype. (C and D) Visualization of HA (green) and cell nuclei (DAPI; blue) in d18 cervices. While HA was completely depleted from Has1/2/3 KO epithelia and mucus (C), low levels of HA were detectable in the stroma of Has2 KO (not shown) and Has1/2/3 KO mice (D), likely derived from progesterone receptor–negative cells. 4 cervices per genotype were evaluated for immunofluorescence. S, stroma; ME, mucosal epithelia (defined as terminally differentiated epithelia with visible mucus-laden vacuoles); NME, nonmucosal epithelia (defined as epithelia with no visible mucus-laden vacuoles); M, mucus; L, cervicovaginal lumen. *P < 0.05, 1-way ANOVA with pairwise multiple comparisons by Tukey test. Scale bars: 20 μm.