Publications

@article{nokey,

title = {Engineering extracellular vesicles to transiently permeabilize the blood–brain barrier},

author = {Francesca Tomatis and Susana Rosa and Susana Simões and Marta Barão and Carlos Jesus and João Novo and Emanuel Barth and Manja Marz and Lino Ferreira},

doi = {10.1186/s12951-024-03019-w},

year  = {2024},

date = {2024-12-02},

journal = {Journal of Nanobiotechnology},

volume = {22},

abstract = {Background

Drug delivery to the brain is challenging due to the restrict permeability of the blood brain barrier (BBB). Recent studies indicate that BBB permeability increases over time during physiological aging likely due to factors (including extracellular vesicles (EVs)) that exist in the bloodstream. Therefore, inspiration can be taken from aging to develop new strategies for the transient opening of the BBB for drug delivery to the brain.

Results

Here, we evaluated the impact of small EVs (sEVs) enriched with microRNAs (miRNAs) overexpressed during aging, with the capacity to interfere transiently with the BBB. Initially, we investigated whether the miRNAs were overexpressed in sEVs collected from plasma of aged individuals. Next, we evaluated the opening properties of the miRNA-enriched sEVs in a static or dynamic (under flow) human in vitro BBB model. Our results showed that miR-383-3p-enriched sEVs significantly increased BBB permeability in a reversible manner by decreasing the expression of claudin 5, an important tight junction protein of brain endothelial cells (BECs) of the BBB, mediated in part by the knockdown of activating transcription factor 4 (ATF4).

Conclusions

Our findings suggest that engineered sEVs have potential as a strategy for the temporary BBB opening, making it easier for drugs to reach the brain when injected into the bloodstream.},

keywords = {aging, extracellular vesicles, ncRNAs},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {The Role of Non-Coding RNAs in the Human Placenta},

author = {Milena Žarković and Franziska Hufsky and Udo R Markert and Manja Marz},

doi = {10.3390/cells11091588},

year  = {2022},

date = {2022-05-09},

journal = {Cells},

volume = {11},

issue = {9},

pages = {1588},

abstract = {Non-coding RNAs (ncRNAs) play a central and regulatory role in almost all cells, organs, and species, which has been broadly recognized since the human ENCODE project and several other genome projects. Nevertheless, a small fraction of ncRNAs have been identified, and in the placenta they have been investigated very marginally. To date, most examples of ncRNAs which have been identified to be specific for fetal tissues, including placenta, are members of the group of microRNAs (miRNAs). Due to their quantity, it can be expected that the fairly larger group of other ncRNAs exerts far stronger effects than miRNAs. The syncytiotrophoblast of fetal origin forms the interface between fetus and mother, and releases permanently extracellular vesicles (EVs) into the maternal circulation which contain fetal proteins and RNA, including ncRNA, for communication with neighboring and distant maternal cells. Disorders of ncRNA in placental tissue, especially in trophoblast cells, and in EVs seem to be involved in pregnancy disorders, potentially as a cause or consequence. This review summarizes the current knowledge on placental ncRNA, their transport in EVs, and their involvement and pregnancy pathologies, as well as their potential for novel diagnostic tools.},

keywords = {extracellular vesicles, ncRNAs, pregnancy, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Small Extracellular Vesicles from Peripheral Blood of Aged Mice Pass the Blood-Brain Barrier and Induce Glial Cell Activation.},

author = {Diana M Morales-Prieto and José M Murrieta-Coxca and Milan Stojiljkovic and Celia Diezel and Priska E Streicher and Julian A Henao-Restrepo and Franziska Röstel and Julia Lindner and Otto W Witte and Sebastian Weis and Christian Schmeer and Manja Marz},

doi = {10.3390/cells11040625},

year  = {2022},

date = {2022-02-11},

journal = {Cells},

volume = {11},

issue = {4},

pages = {625},

abstract = {Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes in EV concentration are reported in aging tissues and senescence cells, suggesting a role of EVs in the process of aging. Here, we investigated the effect of peripheral sEVs from aged animals on neuroinflammation, specifically on glial activation. sEVs were isolated from the peripheral blood of young (3 months) and aged (24 months) C57BL/6J wildtype mice and injected into the peripheral blood from young animals via vein tail injections. The localization of EVs and the expression of selected genes involved in glial cell activation, including Gfap, Tgf-β, Cd68, and Iba1, were assessed in brain tissue 30 min, 4 h, and 24 h after injection. We found that sEVs from peripheral blood of aged mice but not from young mice altered gene expression in the brains of young animals. In particular, the expression of the specific astrocyte marker, Gfap, was significantly increased, indicating a strong response of this glial cell type. Our study shows that sEVs from aged mice can pass the blood-brain barrier (BBB) and induce glial cell activation.},

keywords = {aging, extracellular vesicles},

pubstate = {published},

tppubtype = {article}

}

@article{Morales-Prieto:18a,

title = {Peripheral blood exosomes pass blood-brain-barrier and induce glial cell activation},

author = {Diana M. Morales-Prieto and Milan Stojiljkovic and Celia Diezel and Priska-Elisabeth Streicher and Franziska Roestel and Julia Lindner and Sebastian Weis and Christian Schmeer and Manja Marz},

doi = {10.1101/471409},

year  = {2018},

date = {2018-11-29},

urldate = {2018-11-29},

journal = {bioRxiv},

pages = {471409},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Background Exosomes are involved in intracellular communication and contain proteins, mRNAs, miRNAs, and signaling molecules. Exosomes were shown to act as neuroinflammatory mediators involved in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS). Brain aging has been associated to increased neuroinflammation. In addition, a decreased extracellular vesicle concentration was observed in aging tissues. The specific mechanisms how exosomes and aging are connected are not known yet.



Results Here we have shown that peripheral injection had almost no effect on selected gene expression in the liver. However, exosome injection has led to changes in the specific markers of glial cell activation (CD68, Iba1, GFAP). Interestingly, only injection of exosomes isolated from aged mice induced significant activation of astrocyte cells, as shown by increased GFAP expression.



Conclusion Transcription levels of genes GFAP, TGF-β, CD68, Iba1 known to be involved in glial cell function are significantly changing after introduction of peripheral extracellular vesicles. Exosomes were able to pass blood brain barrier and induce glial cell activation. GFAP known to be a specific astrocyte activation marker was significantly higher expressed after injection of old but not young exosomes, indicating a possible role of exosomes in the mechanisms of brain aging.},

keywords = {aging, extracellular vesicles, liver, ncRNAs},

pubstate = {published},

tppubtype = {article}

}