Astrocytes in the damaged brain: Molecular and cellular insights into their reactive response and healing potential

Abstract

Long considered merely a trophic and mechanical support to neurons, astrocytes have progressively taken the center stage as their ability to react to acute and chronic neurodegenerative situations became increasingly clear. Reactive astrogliosis starts when trigger molecules produced at the injury site drive astrocytes to leave their quiescent state and become activated. Distinctive morphological and biochemical features characterize this process (cell hypertrophy, upregulation of intermediate filaments, and increased cell proliferation). Moreover, reactive astrocytes migrate towards the injured area to constitute the glial scar, and release factors mediating the tissue inflammatory response and remodeling after lesion. A novel view of astrogliosis derives from the finding that subsets of reactive astrocytes can recapitulate stem cell/progenitor features after damage, fostering the concept of astroglia as a promising target for reparative therapies. But which biochemical/signaling pathways modulate astrogliosis with respect to both the time after injury and the type of damage? Are reactive astrocytes overall beneficial or detrimental for neuroprotection and tissue regeneration? This debate has been animating this research field for several years now, and an integrated view on the results obtained and the possible future perspectives is needed. With this Commentary article we have attempted to answer the above-mentioned questions by reviewing the current knowledge on the molecular mechanisms controlling and sustaining the reaction of astroglia to injury and its stem cell-like properties. Moreover, the cellular/molecular mechanisms supporting the detrimental or beneficial features of astrogliosis have been scrutinized to gain insights on possible pharmacological approaches to enhance astrocyte neuroprotective activities.

Introduction

Astrocytes are multifunctional cells that, in addition to play an essential homeostatic role and contribute to information processing in physiological conditions, are capable to mount a response to any kind of insult to the central nervous system (CNS). In their reaction to injury (astrogliosis) they leave their quiescent state and become activated. During this process, they undergo hypertrophy, upregulate intermediate filaments composed of nestin, vimentin, and glial fibrillary protein (GFAP), and activate cell proliferation (Fig. 1 ) [1], [2] (see also below). Moreover, in their reactive state astrocytes can continue to divide, migrate to form the glial scar, and release a plethora of factors mediating the tissue inflammatory response and remodeling after lesion [3], [4]. It is increasingly clear that the modalities and dynamics of the astrocyte response to damage are crucial to the outcome of brain pathology and the degree of neurological damage. In light of these facts, astrogliosis appears to be an appealing therapeutic target for the implementation of endogenous repair in the CNS.

In this review we shall discuss the molecular mechanisms known to regulate astroglia activation and the evolution of the ensuing reactivity. Special focus will be devoted to highlight how functional changes in astroglia influence the lesioned nervous tissue either beneficially or detrimentally with respect to tissue integrity and functional outcome. Furthermore, we shall attempt to compose an integrated picture of this duality, and discuss how the novel stem cell/progenitor aspects of some astroglia subsets, together with the detailed understanding of gliosis regulatory mechanisms, may help in developing strategies for treating the insulted CNS.