Integrins mediate placental extracellular vesicle trafficking to lung and liver in vivo

Abstract

Membrane-bound extracellular vesicles (EVs) mediate intercellular communication in all organisms, and those produced by placental mammals have become increasingly recognized as significant mediators of fetal-maternal communication. Here, we aimed to identify maternal cells targeted by placental EVs and elucidate the mechanisms by which they traffic to these cells. Exogenously administered pregnancy-associated EVs traffic specifically to the lung; further, placental EVs associate with lung interstitial macrophages and liver Kupffer cells in an integrin-dependent manner. Localization of EV to maternal lungs was confirmed in unmanipulated pregnancy using a transgenic reporter mouse model, which also provided in situ and in vitro evidence that fetally-derived EVs, rarely, may cause genetic alteration of maternal cells. These results provide for the first time direct in vivo evidence that placental EVs target maternal immune cells, and further, that EVs can alter cellular phenotype.

Development of Extracellular Vesicle Therapeutics: Challenges, Considerations, and Opportunities

“…Considering that EVs carry and transfer various functional molecular cargo, quantitative global analyses to understand EV-associated components [e.g., EV-mediated transfer of proteins/lipids/RNAs between specific cell types and organs ( Costa-Silva et al, 2015 ; Hoshino et al, 2015 ; Flaherty et al, 2019 ; Rodrigues et al, 2019 ; Kugeratski et al, 2021 ; Nguyen et al, 2021 )] warrants further investigation. Increasingly, the field is shifting toward systems biology to understand EVs ( Xu et al, 2016 ; Gezsi et al, 2019 ), integrating different analysis platforms to achieve multi-omic characterization of EVs for therapeutic application—their source (different donor origins, organ/tissue-derived), composition (including core and surfaceome/interactome landscape), and capacity to reprogram target cells and phenotype ( Hoshino et al, 2015 , 2020 ; Melo et al, 2015 ; Kowal et al, 2016 ; Xu et al, 2016 ; Figueroa et al, 2017 ; Greening et al, 2017 ; Flaherty et al, 2019 ; Rontogianni et al, 2019 ; Xu H. et al, 2019 ; Jung et al, 2020 ; Bijnsdorp et al, 2021 ; Kugeratski et al, 2021 ; Rai et al, 2021 ).…”

“…The mononuclear phagocyte system (MPS) [previously termed reticuloendothelial system (RES)] encompasses monocytes, macrophages, and other cells present in liver, spleen, and lungs, and contributes to EV sequestration and clearance ( Rao et al, 2015 ; Smyth et al, 2015 ). Indeed, following in vivo administration, EVs accumulate in the liver, spleen and/or lung; an occurrence widely observed in EVs derived from dendritic ( Wei et al, 2017 ), MSCs ( Grange et al, 2014 ), myoblasts ( Wiklander et al, 2015 ; Charoenviriyakul et al, 2017 ), kidney ( Lai et al, 2014 ), glial ( Lai et al, 2014 ), melanoma ( Peinado et al, 2012 ; Takahashi et al, 2013 ; Imai et al, 2015 ; Charoenviriyakul et al, 2017 ), macrophages ( Charoenviriyakul et al, 2017 ), and placental ( Tong et al, 2017 ; Nguyen et al, 2021 ) cells. With phagocytosis central to clearance, EVs avoid engulfment through surface presentation of anti-phagocytic signals including immunomodulatory receptors, most commonly CD47 ( Chao et al, 2012 ; Rodriguez et al, 2013 ; Kaur et al, 2014 ; Kamerkar et al, 2017 ; Tang Y. et al, 2019 ), PD-L1 ( Gordon et al, 2017 ; Hsu et al, 2018 ; Cordonnier et al, 2020 ; Daassi et al, 2020 ), CD24 ( Barkal et al, 2019 ), CD31 ( Brown et al, 2002 ), and CD44 ( Vachon et al, 2007 ; Amash et al, 2016 ), that act as “don’t eat me” signals to phagocytic cells, potentially prolonging their EV half-life in circulation.…”

Production and Composition of Group B Streptococcal Membrane Vesicles Vary Across Diverse Lineages

“…The isolation and purification of MVs was performed as described ( Chutkan et al, 2013 ; Klimentová and Stulík, 2015 ; Surve et al, 2016 ; Nguyen et al, 2021 ), with some modifications. Briefly, overnight THB cultures were diluted 1:50 into fresh broth and grown to late logarithmic phase (optical density at 600 nm, OD 600 = 0.9 ± 0.05).…”

“…Nanoparticle tracking analysis was performed to quantify MVs produced by each strain (n = 8-9 replicates per strain) using a NanoSight NS300 (Malvern Panalytical Westborough, MA, United States) equipped with an automated syringe sampler as described previously (Nguyen et al, 2019(Nguyen et al, , 2021. For each sample, MVs were diluted in phosphate buffered saline (1:100-1:1,000) and injected with a flow rate of 50.…”

Impact of chemically defined culture media formulations on extracellular vesicle production by amniotic epithelial cells

“…Changes of MFI levels of tetraspanins reflects the changes in EV biogenesis and thus points to potential functional changes. Various integrins also play important roles in the cell/tissue recognition for EVs[95,96]. CD29 (ITGB1) plays an important role in pro-angiogenesis, cell differentiation, and cell migration[97,98].…”