Signals that trigger labor and delivery
Researchers believe they now know more about what signals the start of labor and delivery, perhaps better understanding triggers of preterm delivery.
In a normal full-term pregnancy, signals from the mature organs of the fetus and from the aging placenta, prompt the uterine muscular walls to begin labor. It's still unclear how these signals accomplish this goal or how they reach from the fetal side to the maternal side.
A team from The University of Texas Medical Branch at Galveston (UTMB) has unlocked key clues in understand what triggers the birthing process, according to research findings recently published in PLOS ONE.
"It's important that we better understand how signals interact in normal full-term pregnancies as it may provide insights into how and why they can activate early and trigger labor and delivery prematurely."
Ramkumar Menon PhD, Assistant Professor, University of Texas Medical Branch at Galveston, Texas, USA, Department of Obstetrics and Gynecology, and lead author.
According to the World Health Organization, an estimated 15 million babies are born preterm, or before 37 weeks of pregnancy, each year. Complications from preterm birth are the chief cause of death among children under five.
UTMB researchers studied the production and movement of exosomes, cell derived molecular bubbles that contain chemical signals and transport those signals between cells. Exosomes are present in many and perhaps all biological fluids, including blood, urine, and the cultured medium of petri dishes. Their diameter is between 30 and 100 nm, much smaller than red blood cells.
The exosomes for this study came from the amnion's epithelial cells (AECs) — the inner lining of the placenta form a cavity close to the fetus as amnion cells protect the fetus during its growth in utero. AECs were isolated from the discarded placental tissue of women who delivered via cesarean section, full-term without going into labor, in order to examine the content of the exosomes.
Once separated out, a portion of the AEC-derived exosomes were exposed to stress via cigarette smoke, for 48 hours. Next, the contents of the normal and stressed exosomes were charted and compared using various techniques.
Researchers found stressed exosomes contain the p38 MAPK molecule, known to be linked to delivery by speeding up placental aging and increasing inflammation of the uterus.
Uterine inflammation stops the hormone progesterone, prompting uterine contractions — even when the fetus is not fully developed.
At term, the signals of fetal maturity and feto-placental tissue aging prompt uterine readiness for delivery by transitioning quiescent myometrium to an active stage. It is still unclear how the signals reach the distant myometrium. Exosomes are a specific type of extracellular vesicle (EVs) that transport molecular signals between cells, and are released from a wide range of cells, including the maternal and fetal cells. In this study, we hypothesize that i) exosomes act as carriers of signals in utero-placental compartments and ii) exosomes reflect the physiologic status of the origin cells. The primary aims of this study were to determine exosomal contents in exosomes derived from primary amnion epithelial cells (AEC). We also determined the effect of oxidative stress on AEC derived exosomal cargo contents. AEC were isolated from amniotic membrane obtained from normal, term, not in labor placentae at delivery, and culture under standard conditions. Oxidative stress was induced using cigarette smoke extract for 48 hours. AEC-conditioned media were collected and exosomes isolated by differential centrifugations. Both growth conditions (normal and oxidative stress induced) produced cup shaped exosomes of around 50 nm, expressed exosomes enriched markers, such as CD9, CD63, CD81 and HSC70, embryonic stem cell marker Nanog, and contained similar amounts of cell free AEC DNA. Using confocal microscopy, the colocalization of histone (H) 3, heat shock protein (HSP) 70 and activated form of pro-senescence and term parturition associated marker p38 mitogen activated protein kinase (MAPK) (P-p38 MAPK) co-localized with exosome enrich marker CD9. HSP70 and P-p38 MAPK were significantly higher in exosomes from AEC grown under oxidative stress conditions than standard conditions (p<0.05). Finally, mass spectrometry and bioinformatics analysis identified 221 different proteins involved in immunomodulatory response and cell-to-cell communication. This study determined AEC exosome characteristics and their cargo reflected the physiologic status of the cell of origin and suggests that AEC-derived exosomal p38 MAPK plays a major role in determining the fate of pregnancy. Understanding the propagation of fetal signals and their mechanisms in normal term pregnancies can provide insights into pathologic activation of such signals associated with spontaneous preterm parturitions.
Other authors include UTMB's Samantha Sheller, John Papaconstantinou, Rheanna Urrabaz-Garza, Lauren Richardson and George Saade as well as Carlos Salomon from the University of Queensland in Herston, Australia.
Return to top of page
Aug 9, 2016 Fetal Timeline Maternal Timeline News News Archive
The molecule p38 MAPK was identified in amnion exosomes, foretelling an early delivery.
Image Credit: public domain