Glial cells were identified for the first time in the nineteenth century when the French physician René Dutrochet described for the first time, in 1824, small globules among the large ones within the mollusk nervous system. However, we have to wait until 1856 when the German pathologist Rudolph Virchow coined the term “nervekitt,” nerve glue, to describe that sort of connective tissue of the central nervous system. Subsequently, Santiago Ramon y Cajal, Pio del Rio Hortega, and Otto Deiters pioneered this field with their experiments and gave them the name “glia” derived from the ancient Greek word that means glue. At that time, glia was considered as purely unfunctional glue for neurons . However, research since the mid-1990 has shown that glia might play a particularly important role in the cognitive function as indicated by the correlation between the glia/neuron ratio in brain tissue and the state of evolution of species . In fact,
Indeed, even if several neuropathologists, such as Alzheimer, Nissl, and Fromman, speculate a glial role in neurodegenerative disorders, until the mid-1990s, the neurocentric paradigm dominated. Nevertheless, growing evidences indicate that astroglial dysfunction contributes to the pathogenesis of several neurological and psychiatric disorders . A common feature of several neurological diseases is reactive astrogliosis.
2. Reactive astrogliosis
Reactive astrogliosis is a spectrum of changes in astrocytes that occur in response of all forms of CNS injury and disease. In summary, injured tissues display upregulation of structural proteins, such as glial fibrillary acidic protein (GFAP) and vimentin, and hypertrophy of astrocytes’ cell body and processes that elongate around the lesion core and release a cascade of inflammatory signals that can strongly affect the pathological outcome . Moreover, some quiescent astrocytes re-enter the cell cycle . However, these hallmarks can vary according to the severity of the disease and are regulated by inter- and intracellular signaling molecules in a context-specific manner . In particular, in mild or moderate astrogliosis, which generally occurs far from CNS focal lesions, astrocytic proliferation is almost absent and the increased GFAP expression together with cell body and process hypertrophy, which is not altering astrocyte organization into individual distinct domains, are variable . Moreover, moderate astrogliosis also results in the expression of copper-zinc superoxide dismutase, glutathione peroxidase or metallothionein, inducible nitric oxide synthase, and release of trophic factors and cytokines, including tumor necrosis factor and interleukins and interferons . Furthermore, in mild or moderate forms, if the initial triggering insult is removed, reactive astrogliosis can revert and cells return to a condition similar to that observed in healthy tissue . On the other hand, near focal lesions, severe diffuse astrogliosis is characterized by significantly increased astrocytic proliferation. The molecular factors that induce astrocytes’ proliferation are not completely characterized, but several studies ascribe an important role to epidermal growth factor, fibroblast growth factor, endothelin 1, ATP, lipopolysaccharide, and nitric oxide [18, 19, 20, 21]. Astrocytic proliferation causes overlapping of neighboring astrocytic processes with the disruption of the individual astrocyte domains and the consequent formation of a compact glial scar. Such scar, which represents the hallmark of reactive astrogliosis, is due to astrocyte interaction with different cell types of the brain tissue and is characterized by phenomena of necrosis, tumors, chronic neurodegeneration, infection, or inflammatory infiltration [15, 21]. These structural changes are not reversible and persist also after the resolution of the triggering insult . More important, mature glial scars act as barriers to inflammatory cells to protect surrounding healthy tissue from nearby areas of intense inflammation. Reactive astrocytes can also protect CNS cells and tissue by up-taking excitotoxic glutamate, producing glutathione against oxidative stress, degrading amyloid-beta peptides, regulating extracellular space volume and ion balance, facilitating blood-brain barrier repair, and regulating CNS inflammation. Nevertheless, growing evidence also shows that reactive astrocytes can contribute to or be the primary source of CNS physiopathology. Reactive astrocytes from glial scars can indeed synthesize collagen and sulfate proteoglycans, which prevent axon regeneration .
3. Astrocytes: new tools for neurological disease research
Traditionally, astrocytes have been studied as a homogeneous group of cells, even if the peculiar morphology of mature mammalian astrocytes was observed since 1865 thanks to the studies on mouse brain by Otto Deiters . A detailed morphological study of glial cells came from Camillo Golgi and Ramon y Cajal in 1872 who, independently, by means of the black staining reaction, observed two different types of astrocytes: the protoplasmic and the fibrous astrocytes. However, for a long time, astrocytes received little or no consideration as target for neurological studies because the neurocentric paradigm dominated. New and recent findings demonstrated that astrocytes are positioned to promote both the regeneration of the damaged neurons and to protect existing neurons from degeneration. For this reason, astrocytes represent an important focus in the development of new therapeutic tools for neurodegenerative disorder that have been historically viewed as purely neuronal in their pathology. Within the past 5 years, important progress has been made deriving astrocytes from induced pluripotent stem cells (IPSC). Researchers are now able to generate patients-specific astrocytes that recapitulate the patients’ genetic background. Once healthy astrocytes have been obtained and characterized, they can be used to replace dying astrocytes or to promote the survival of existing neurons. This kind of application has not yet been tested in humans; however, there is a growing body of