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Review
. 2022 Jan:347:113914.
doi: 10.1016/j.expneurol.2021.113914. Epub 2021 Nov 6.

Placental mediated mechanisms of perinatal brain injury: Evolving inflammation and exosomes

Alexander R Gall  1 , Stephen Amoah  1 , Yuma Kitase  1 , Lauren L Jantzie  2
Affiliations
Review

Placental mediated mechanisms of perinatal brain injury: Evolving inflammation and exosomes

Alexander R Gall et al. Exp Neurol. 2022 Jan.

Abstract

Pregnancy is an inflammatory process that is carefully regulated by the placenta via immunomodulation and cell-to-cell communication of maternal and fetal tissues. Exosomes, types of extracellular vesicles, facilitate the intercellular communication and traffic biologically modifying cargo within the maternal-placental-fetal axis in normal and pathologic pregnancies. Chorioamnionitis is characterized by inflammation of chorioamniotic membranes that produces systemic maternal and fetal inflammatory responses of cytokine dysregulation and has been associated with brain injury and neurodevelopmental disorders. This review focuses on how pathologic placental exosomes propagate acute and chronic inflammation leading to brain injury. The evidence reviewed here highlights the need to investigate exosomes from pathologic pregnancies and those with known brain injury to identify new diagnostics, biomarkers, and potential therapeutic targets.

Keywords: Chorioamnionitis; Exosomes; Inflammatory signal transduction; Perinatal brain injury.

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Figures

Fig. 1.
Fig. 1.
Placental-derived mediators drive neural injury in CHORIO. Sham or CHORIO placental explants were cultured on inserts and placental conditioned media (PCM) assayed for toxic mediators and inflammatory drivers (A-B). CHORIO placentas secrete more IL-1β (A), and TNF-α (B) compared to sham placentas. To determine the effect of CHORIO PCM on the developing brain, PCM from naive or CHORIO placental explants was cultured with postnatal day 2 (P2) brain slices (C). PCM from CHORIO placental explants induced high levels of CXCL1 in P2 brain slices. (n = 4–5, two independent experiments, *p < 0.05, **p < 0.01, ***p < 0.001).
Fig. 2.
Fig. 2.
Placental-derived exosomes drive neural injury in CHORIO. To confirm whether cytokines themselves or placental-derived exosomes were able to induce brain CXCL1 expression, exosomes were isolated from CHORIO PCM (A). Exosomes from CHORIO placentae elevated CXCL1 mRNA in P2 brain slices (A - purple bar). Notably, cerebral CXCL1 mRNA levels were reduced by blockade of exosome release using the exosome generation inhibitor GW4869 (A - gray and black bars). Blockade of placental exosome generation also improved neural cell health and preserved developmental trajectory (B). Specifically, GABAARɣ2 mRNA was increased in P2 brain slices cultured with exosome depleted PCM compared to exosome containing PCM (B). (n = 4–5, two independent experiments, *p < 0.05, **p < 0.01, ***p < 0.001. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3.
Fig. 3.
Placental-derived exosomes as a plausible pathophysiological mechanism in perinatal brain injury.
See this image and copyright information in PMC

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