Exosomes released by glioblastoma stem cells activate astrocytes and induce the acquisition of a neural stem cell potential by glial cells

Cellular heterogeneity and plasticity is a hallmark of glioblastoma multiforme and the role played by the surrounding microenvironment is considered to be crucial for the tumor progression. Recent findings suggest that the glioblastoma microenvironment is populated by astrocytes that undergo a process of activation acquiring properties characterizing reactive gliosis, along with the acquisition or re-activation of a stem cell potential. However, communication processes occurring among the different cell types populating the glioblastoma microenvironment are largely unclear. We evaluated the possibility that exosomes produced by glioblastoma cells could modulate the biological properties of normal astrocytes inducing an activated phenotype and stem-like features. The results obtained indicate that glioblastoma cells, both derived from a commercial cell line or primary cultured cells, are capable of inducing the activation of astrocytes by means of exosomes release. Indeed, after being grown in the presence of these latter, astrocytes acquire morphological, functional and phenotypic features distinguishing the phenotype of reactive astrocyte. However, only exosomes released by glioblastoma stem cells (GSC) promote the de-differentiation of normal human astrocytes, increasing their growth efficiency as spherical aggregates in suspension. These neurospheres, here called “astrospheres”, possess neural stem cell-like features, being able to express neural stem cell markers, and to differentiate into neuronal, glial and oligodendroglial lineages. Moreover, “astrospheres” obtained from astrocytes grown in culture in the presence of exosomes released by glioblastoma stem cells were able to spontaneously differentiate into functional radial glia-like cells, characterized by the expression of both neuroepithelial and astroglial markers and by the ability to support the migration of immature neurons, thus suggesting a possible mechanism through which glioblastoma cells infiltrate the brain parenchyma