Extracellular vesicle mediated feto-maternal HMGB1 signaling induces preterm birth
Autor: | Rheanna Urrabaz-Garza, Ananth K. Kammala, Ramkumar Menon, Samantha Sheller-Miller, Talar Kechichian, Arum Han, Lauren S. Richardson, Tuvshintugs Baljinnyam, Enkhtuya Radnaa, Sungjin Kim, Mariana de Castro Silva |
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Rok vydání: | 2021 |
Předmět: |
Receptor expression
Biomedical Engineering Bioengineering Biology Exosomes Biochemistry Exosome Article Mice 03 medical and health sciences Paracrine signalling chemistry.chemical_compound 0302 clinical medicine Pregnancy medicine Animals Decidual cells HMGB1 Protein 030304 developmental biology 0303 health sciences 030219 obstetrics & reproductive medicine Amnion Decidua Reproducibility of Results Carboxyfluorescein succinimidyl ester General Chemistry Extracellular vesicle Cell biology medicine.anatomical_structure chemistry embryonic structures Premature Birth Female Signal Transduction |
Zdroj: | Lab Chip |
ISSN: | 1473-0189 1473-0197 |
Popis: | Preterm birth (PTB; < 37 weeks of gestation) impacts ~ 11% of all pregnancies and contributes to 1 million neonatal deaths worldwide annually. An understanding of the feto-maternal (F-M) signals that initiate birthing (parturition) at term is critical to design strategies to prevent their premature activation, resulting in PTB. Although endocrine and immune cell signaling are well-reported, fetal-derived paracrine signals capable of transitioning quiescent uterus to an active state of labor are poorly studied. Recent reports have suggested that senescence of the fetal amnion membrane coinciding with fetal growth and maturation generates inflammatory signals capable of triggering parturition. This is by increasing the inflammatory load at the feto-maternal interface (FMi) tissues (i.e., amniochorion-decidua). High mobility group box 1 protein (HMGB1), an alarmin, is one of the inflammatory signals released by senescent amnion cells via extracellular vesicles (exosomes; 40–160 nm). Increased levels of HMGB1 in the amniotic fluid, cord and maternal blood are associated with term and PTB. This study tested the hypothesis that senescent amnion cells release HMGB1, which is fetal signaling capable of increasing FMi inflammation, predisposing them to parturition. To test this hypothesis, exosomes from amnion epithelial cells (AECs) grown under normal conditions were engineered to contain HMGB1 by electroporation (eHMGB1). eHMGB1 was characterized (quantity, size, shape, markers and loading efficiency), and its propagation through FMi was tested using a four-chamber microfluidic organ-on-a-chip device (FMi-OOC) that contained four distinct cell types (amnion and chorion mesenchymal, chorion trophoblast and decidual cells) connected through microchannels. eHMGB1 propagated through the fetal cells and matrix to the maternal decidua and increased inflammation (receptor expression [RAGE and TLR4] and cytokines). Furthermore, intra-amniotic injection of eHMGB1 (containing 10 ng) into pregnant CD-1 mice on embryonic day 17 led to PTB. Injecting carboxyfluorescein succinimidyl ester (CFSE)-labeled eHMGB1, we determined in vivo kinetics and report that eHMGB1 trafficking resulting in PTB was associated with increased FMi inflammation. This study determined that fetal exosome mediated paracrine signaling can generate inflammation and induce parturition. Besides, in vivo functional validation of FMi-OOC experiments strengthens the reliability of such devices to test physiologic and pathologic systems. |
Databáze: | OpenAIRE |
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