A Birth Story: Cortisol-Stimulated Autophagy in Parturition

It has been estimated that 14.9 million preterm infants are born each year, and the mortality rates among these infants account for 35% of the 3.1 million global neonatal deaths annually (1, 2). The right timing of birth is a major determinant of pregnancy success and in most species is the result of coordinated maternal and fetal signals (3). Appropriately timed parturition depends on the fetal membranes maintaining their physical integrity; failure to do so leads to preterm premature rupture of the membranes and delivery of a preterm infant. Human fetal membranes comprise two concentric cellular layers; on the fetal side lies the amnion and on the outside lies the chorion. The amnion, and stronger of the two membranes, is composed of a single layer of cuboidal epithelium that is supported by a basement membrane resting on a thick collagen layer enriched with fibroblasts. The outer chorion is a much thicker layer composed of the extraembryonic mesoderm and trophoblasts that are directly connected to the maternal decidua (4). In early pregnancy, the amnion and chorion exist as separate membranes but fuse between 14 and 16 weeks of gestation. In term pregnancies, the rupture of human fetal membranes involves a number of well-coordinated spatial and temporal events that include the structural preweakening of the membranes resulting from changes in the extracellular matrix (ECM) composition, followed by cellular apoptosis in the paracervical region, a focal area overlying the cervix (5–9). This is associated with a separation of the amnion from the choriodecidua and represents an important component in the weakening of the membranes (10). Timed with these membrane-localized events is the functional progesterone withdrawal in the myometrium that leads to increased myometrial contraction that softens the cervical ECM, resulting in distension and dilatation and a shearing of the preweakened fetal membranes, triggering their rupture. The tensile strength of the membranes results from the composition of the collagen subtypes. Collagen is the major protein component of the ECM, and the fetal membranes consist mainly of type I, III, and V collagens arranged in a complex framework to promote maximum mechanical resistance. Among these three types of collagen, it is widely accepted that the greatest support is derived from fibers composed of types I and III collagen, and these are stabilized by collagen type V. Additional stabilization is also derived from the less abundant collagens, types IV and VI (4). The observation that preterm labor in humans is marked by pronounced changes in the composition and/or distribution of ECM proteins in fetal membranes has been well-established for many years (11–14). This led Guller et al. (15) to determine whether the increase in the levels of glucocorticoids (GCs) in amniotic fluid, a major event associated with both term and preterm labor, modulated the expression of the highly expressed ECM proteins, fibronectin, and collagen III in cultures of human amnion epithelial cells. Their study found that dexamethasone (a synthetic GC closely related to the naturally occurring GC, cortisol) reduced fibronectin and collagen III levels, leading them to conclude that GCs negatively regulate ECM protein expression in amnion epithelial cells, suggesting that a link exists between GCs and preterm premature rupture of the membranes. GCs, of which cortisol is the major biologically active natural form in humans (16), are a class of steroid hormones mainly produced in the zona fasciculata of the adrenal cortex. GCs regulate a number of vital functions in the body, and these include the immune system. In pregnancy, they also play a major role in fetal lung and cardiac development. In utero, in addition to the de novo synthesis of GCs by the adrenal glands, GCs are produced in the fetal membranes, and other GCs target sites from inactive precursors through the action of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In fetal membranes, 11β-HSD1-derived cortisol is a part of the machinery that, near the end of pregnancy, promotes fetal organ maturation and likely, as shown by increasing evidence, the structural remodeling, reduction in collagen content, and weakening of the amnion, which leads to the initiation of parturition (17–19). Previous studies aimed at understanding the mechanisms underlying the reduction in fetal membrane collagen focused mostly on their degradation by matrix metalloproteases (20–23), and until recently, it was not known what role, if any, autophagy plays in this reduction. However, a brilliant study published in this issue of Endocrinology has demonstrated most convincingly that such a role likely exists (24). Investigators have hypothesized that because GCs regulate lysosome-mediated autophagy in other tissues and organs (25–27), coupled with the 11β-HSD1–dependent feed-forward nature of cortisol regeneration in human fetal membranes (28, 29), the rupture of fetal membranes likely occurs through induction of the autophagic degradation of collagens. In their study, Mi et al. (24) tested their hypothesis in primary human amnion fibroblasts, a major source of collagens, focusing their attention on type 1 collagen, which consists of two α1 chains (COL1A1) and one α2 chain (COL1A2) (30). In strong support of their hypothesis, Mi et al. (24) demonstrated that treatment of human amnion fibroblasts with cortisol had no effect on COL1A and COL1A2 messenger RNA levels. However, in a concentration- and time-dependent manner, cortisol significantly reduced COLA1 and COL1A2 protein abundance in a GC receptor (GR)-dependent manner. Furthermore, they provided evidence that this reduction occurs at a post-translational level. To explore this observation further, they determined whether the amnion fibroblasts showed a cortisol-dependent increase in the LC3II/LC3I ratio, the marker of lysosome activation (24). Not only did it increase, suggesting a role for the degradation of cytoplasmic components within lysosomes (autophagy), but also, the decrease was GR-dependent, suggesting that cortisol might have reduced COLA1 and COL1A2 protein levels via lysosomal activation downstream of GR activation. However, in the presence of the lysosome inhibitor CQ or downregulation of autophagy-related protein 7, the cortisol-induced reduction in COL1A1 was completely blocked. However, interestingly, the COL1A2 levels were unaffected. These data strongly suggest that the cortisol-induced reduction in COL1A1 occurs through lysosome-mediated autophagy but COL1A2 is not affected. Next, Mi et al. (24) demonstrated that the cortisol-dependent decrease in COL1A1 and COL1A2 protein abundance in primary amnion fibroblasts could be recapitulated in cortisol-treated human amnion tissue explants. At an ultrastructural level, they observed that, relative to control explants, in cortisol-treated samples, the abundance of collagen appeared reduced, with collagen fibrils exhibiting a disorganized and dispersed spatial distribution. Finally, Mi et al. (24) determined that in the amniotic membrane obtained after spontaneous labor, COL1A1 and COL1A2 protein abundance was reduced compared with the levels in the amniotic membrane obtained after cesarean section without labor. These important findings reported by Mi et al. (24) build on a plethora of earlier studies from Drs. Leslie Myatt and Kang Sun and a pivotal study by Guller et al. (15). Together, these findings strengthen the idea of a major role for cortisol in the remodeling of the amnion, a necessary step to ensure timely parturition. Furthermore, the study by Mi et al. (24) provides important mechanistic insights into how cortisol, in a GR-dependent manner, achieves this remodeling and highlights the importance of autophagy in this process. Moving forward, much still remains to be understood about how GR activation triggers an increase in the LC3II/LC3I ratio to stimulate lysosomal degradation of COL1A1 and what mechanisms underlie COL1A2 reduction. It will also be important to determine whether other regulators of parturition modulate this process to affect the timing of parturition in the healthy and pathological states. 11β-hydroxysteroid dehydrogenase type 1 extracellular matrix glucocorticoid glucocorticoid receptor. M.B. is supported by grants from the Canadian Institutes of Health Research (Grant MOP107972), Canadian Institutes of Health Research New Investigator’s Award, and the Early Researcher Award from the Ministry of Research and Innovation, Ontario, Canada. A.V.B. is supported by the Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Child Health Institute of New Jersey, Rutgers University. Disclosure Summary: The authors have nothing to disclose.

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