Professor of Intercellular Communication, Faculty of Veterinary Medicine, University of Utrecht, Netherlands
Marca Wauben is a pioneer in EV-mediated communication and an internationally recognized expert in EV-biology, isolation and characterization. Wauben has investigated EV-mediated communication in different systems and models, evaluated possible clinical applications of EVs and developed technology for EV characterization and isolation. The Wauben EV Lab unveiled novel aspects of EV-mediated communication involved in immune regulation and on the regulation of EV release, EV cargo (proteins, RNAs and lipids) and targeting. Within the STW-UU-Nutricia partnership project (Wauben PI), an isolation method for nano-sized EVs from human milk was developed and proteomic analysis of EVs led to the identification of a ‘novel functional milk proteome’, while with the ZonMW Enabling Technology grant the RNA content of milk-derived EVs was analysed. The Wauben lab discovered that milk EVs have immune modulatory capacities and can increase epithelial barrier formation and they pioneered in single EV-based flow cytometric analysis. Besides investigating fundamental cell biological/immunological aspects, they search for EV-based biomarkers and therapeutic applications of EVs. Wauben is actively involved in many national and global initiatives to build strong scientific EV-biology communities
Deciphering the physiological role of extracellular vesicles in milk:
A One health approach
In mammals, milk is the first functional food and contains different components playing a role in the development of the gastrointestinal tract and immune system. One of these components are extracellular vesicles (EVs), i.e. cell-derived vesicles used for cell-cell communication. Comparative milk EV studies unveiled that miRNA and protein cargoes are highly conserved between species. The fact that milk EVs are stable and can cross epithelial borders has suggested that these EVs are involved in inter-organism communication. However, their role in developmental processes has been poorly studied. We explored the molecular mechanism of human mature milk EV-induced modulation of different cell types present in the gastrointestinal tract and found, by using a re-epithelialization gap closure assay, that milk EVs promote migration of oral epithelial cells. Functional integrative proteomic analysis unveiled hotspots of regulation in the p38 MAPK pathway targeted by milk EV proteins. Milk EVs also inhibited innate immune responses, e.g. agonist-induced endosomal Toll-like receptor 3 (TLR3) triggering of oral cavity epithelial cells, and adaptive immune responses, e.g. inhibition of αCD3/αCD28-induced CD4+ T cell activation, which could be linked to the presence of EV proteins targeting hotspots of regulation resulting in cell-cycle inhibition and mTOR stimulation. Interestingly, raw bovine milk-derived EVs could also inhibit human CD4+ T cell responses, indicating the conserved and cross-species activity of milk EVs. In conclusion, EVs are conserved bioactive structures in mature milk that can modulate canonical signal transduction pathways involved in key processes in the development of the epithelial barrier and the immune system of the new-born.