Abstract
Astrocytes are very versatile cells, endowed with multitasking capacities to ensure brain homeostasis maintenance from brain development to adult life. It has become increasingly evident that astrocytes play a central role in many central nervous system pathologies, not only as regulators of defensive responses against brain insults but also as primary culprits of the disease onset and progression. This is particularly evident in some rare leukodystrophies (LDs) where white matter/myelin deterioration is due to primary astrocyte dysfunctions. Understanding the molecular defects causing these LDs may help clarify astrocyte contribution to myelin formation/maintenance and favor the identification of possible therapeutic targets for LDs and other CNS demyelinating diseases. To date, the pathogenic mechanisms of these LDs are poorly known due to the rarity of the pathological tissue and the failure of the animal models to fully recapitulate the human diseases. Thus, the development of human induced pluripotent stem cells (hiPSC) from patient fibroblasts and their differentiation into astrocytes is a promising approach to overcome these issues. In this review, we discuss the primary role of astrocytes in LD pathogenesis, the experimental models currently available and the advantages, future evolutions, perspectives, and limitations of hiPSC to study pathologies implying astrocyte dysfunctions.
Highlights
LDs were thought to be caused by mutations in oligodendrocyte specific genes, but the identification of some LDs caused by mutations in astrocyte unique genes, such as the glial fibrillary acidic (GFAP) gene in Alexander disease (AxD) and MLC1 in Megalencephalic leukoencephalopathy with subcortical cyst disease (MLC), completely changed this view
Alexander disease (AxD, Figure 2) represents the first example of an LD caused by a primary astrocyte dysfunction [68,69] since it is caused by sporadic dominant mutations in the GFAP gene encoding the GFAP protein [68], the astrocyte-specific marker
Another pathological aspect of Vanishing White Matter (VWM) is the absence of astrogliosis and microglia activation, that it causes an impaired secretion of cytokines supporting oligodendrocyte progenitor cells (OPC) differentiation, oligodendrocyte survival, and myelin formation [125]
Summary
Evidence accumulated in the last 20 years have expanded this initial classification, revealing that astrocytes are a more heterogeneous group of cells showing regional specificities manifested by morphological, molecular and functional differences and whose knowledge is still to be completed [5,6] By extending their processes and end-feet along blood vessels, perivascular astrocytes take part to the formation of the blood-brain-barrier (BBB), the anatomic and biochemical barrier facilitating the entry of nutrients and excluding harmful substances into the brain [7,8,9]. Astroglia contributes to neuron/synapsis development and function, oligodendrocyte/myelin formation and maintenance, neurotransmitter/ionic homeostasis control, blood–brain barrier formation and biochemical properties and immune response regulation [14,15,16,17] To exert these complex tasks and in response to physiological signals, astrocytes can undergo reversible variations in morphology and gene expression profile according to CNS specific functional, temporal, and regional needs, a process called “astrocyte activation” [18]. Astrocyte defects have been found to contribute to the onset, progression, and resolution of numerous diseases, including trauma, infections, neurodegenerative, neuroinflammatory, neurodevelopmental and neuropsychiatric diseases [22,23,24,25,26]
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