Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Extracellular Vesicles Trigger Atp Release and Promote Migration of Human Microglia through the p2x4 Receptor / Mfg-e8 – Dependent Mechanisms

Ugnė Jonavičė
,
Diana Romenskaja
ORCID logo ,
Karolina Kriaučiūnaitė
ORCID logo ,
Akvilė Jarmalavičiūtė
,
Justina Pajarskienė
,
Vytautas Kašėta
,
Virginijus Tunaitis
,
Tarja Malm
,
Rashid Giniatulin
,
Augustas Pivoriūnas
* ORCID logo
Version 1 : Received: 21 June 2021 / Approved: 22 June 2021 / Online: 22 June 2021 (08:26:41 CEST)

A peer-reviewed article of this Preprint also exists.

Jonavičė, U.; Romenskaja, D.; Kriaučiūnaitė, K.; Jarmalavičiūtė, A.; Pajarskienė, J.; Kašėta, V.; Tunaitis, V.; Malm, T.; Giniatulin, R.; Pivoriūnas, A. Extracellular Vesicles from Human Teeth Stem Cells Trigger ATP Release and Promote Migration of Human Microglia through P2X4 Receptor/MFG-E8-Dependent Mechanisms. Int. J. Mol. Sci. 2021, 22, 10970. Jonavičė, U.; Romenskaja, D.; Kriaučiūnaitė, K.; Jarmalavičiūtė, A.; Pajarskienė, J.; Kašėta, V.; Tunaitis, V.; Malm, T.; Giniatulin, R.; Pivoriūnas, A. Extracellular Vesicles from Human Teeth Stem Cells Trigger ATP Release and Promote Migration of Human Microglia through P2X4 Receptor/MFG-E8-Dependent Mechanisms. Int. J. Mol. Sci. 2021, 22, 10970.

Abstract

Extracellular vesicles (EVs) effectively suppress neuroinflammation and induce neuroprotective effects in different disease models. However, the mechanisms by which EVs regulate neuroinflammatory response of microglia remain largely unexplored. Here, we addressed this issue by testing the action of EVs derived from human exfoliated deciduous teeth stem cells (SHEDs) on immortalized human microglial cells. We found that EVs induced a rapid increase in intracellular Ca2+ and promoted a significant ATP release in microglial after 20 min of treatment. Boyden chamber assays revealed that EVs promoted microglial migration by 20 %. Pharmacological inhibition of different subtypes of purinergic receptors demonstrated that EVs activated microglial migration preferentially through the P2X4R pathway. Proximity ligation and co-immunoprecipitation assays revealed that EVs promote association between milk fat globule-epidermal growth factor-factor VIII (MFG-E8) and P2X4 receptor proteins. Furthermore, pharmacological inhibition of αVβ3/αVβ5 integrin suppressed EV -induced cell migration and formation of lipid rafts in microglia. These results demonstrate that EVs promote microglial motility through P2X4 R/ MFG-E8 – dependent mechanisms. Our findings provide novel insights into the molecular mechanisms through which EVs target human microglia that may be exploited for the development of new therapeutic strategies targeting disease associated neuroinflammation.

Keywords

Microglia; Extracellular vesicles; migration; P2X4 receptor; MFG-E8; lipid rafts

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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