Acta Neuropathol (2010) 119:7–35 structural, and potentially functional diversity of astro- cytes at both the regional and local levels, but such investigations are at an early stage [10, 96]. In this con- text it is interesting to note that the number, complexity, and diversity of astroglial cells associated with neurons has increased considerably with evolution, such that the ratio of astrocytes to neurons is 1:6 in worms, 1:3 in rodent cortex, and 1.4:1 in human cortex, implying that astrocyte roles increase in importance with sophistication of neural tissue [162]. The human cerebral neocortex contains multiple subtypes of astrocytes, including types that do not appear to exist in rodent cortex [170]. As molecular markers become more sophisticated, it seems likely that astrocytes will be revealed to be considerably more heterogeneous than thus far imagined. Such infor- mation is likely to impact on concepts about astrocyte roles in both health and disease. GFAP-expressing multipotent radial neural stem cells in juvenile and adult brain Recent studies have identiﬁed speciﬁc morphological and chemical phenotypes of neural stem cells (NSC) in embryonic, juvenile, and adult brain. In the embryonic brain, it is now clear that radial cells are NSC that give rise to cortical pyramidal neurons [116, 134, 164]. As these radial cells mature, they adopt GFAP expression and some give rise to GFAP-expressing radial NSC that persist in juvenile and adult forebrain, while others become astrocytes [116, 122, 142]. Some GFAP- expressing radial NSC remain constitutively active throughout life in the subependymal (or subventricular) zone of the lateral ventricles and in the subgranular zone of the hippocampal dentate gyrus, where they are the predominant source of adult neurogenesis [56, 78, 103, 214]. Based almost entirely on the observation that these adult NSC express GFAP, they have been referred to by some authors as a ‘sub-type’ of astrocyte [56, 116], but it is not clear that such a nomenclature is either war- ranted or useful [14, 84, 153]. There is ample evidence that GFAP is not an exclusive marker of astrocytes. Moreover, as described above, protoplasmic and ﬁbrous astrocytes are highly differentiated and specialized cells that exert a wide variety of complex activities essential for neural function in the healthy CNS, and at present there is no evidence that GFAP-expressing adult radial NSC exert any of the complex functions of mature dif- ferentiated protoplasmic and ﬁbrous astrocytes. In addition, there is clear evidence that mature adult astrocytes are not neurogenic. Differentiated astrocytes in uninjured mature cerebral cortex do not exhibit neuro- genic potential either in vivo or in vitro [104]. Even proliferating reactive astrocytes after CNS trauma give 13 rise only to other astrocytes and do not spontaneously exhibit multipotent neurogenic potential unless they are reprogrammed genetically or by exposure to high doses of speciﬁc growth factors in vitro [29, 30]. In addition, GFAP-expressing NSC differ in morphology (radial phenotype), chemical phenotype (LeX and nestin expression), and physiological characteristics from pro- toplasmic and ﬁbrous astrocytes [78, 104, 126]. Thus, the majority of currently available evidence argues that juvenile and adult NSC share more similarities with embryonic radial NSC than with mature astrocytes. There seems to be no reason to label the multipotent neural progenitors that persist throughout life as a sub- type of astrocyte, which risks the blurring of clear functional distinctions among cell types. Instead, it seems that clarity would best be served by referring to these progenitors simply as either juvenile or adult radial NSC, in keeping with their derivation and phenotype. It has been argued that it may be useful to return to the nomenclature of early neuroanatomists who referred to such radial progenitor cells as ‘neuroepithelial cells’ rather than glia [14, 153]. Regardless of nomenclature, the presence in certain forebrain areas of GFAP- expressing cells that have constitutive multipotent NSC potential throughout life has important implications for concepts regarding various CNS disorders, in particular CNS neoplasms, as discussed below. Astrocyte related cells outside of the CNS There are many cells that have morphological and functional similarities to astrocytes outside of the CNS in both neural and non-neural tissues. Peripheral ganglia contain satellite cells that express GFAP and envelope neurons. Peripheral nerves contain non-myelinating Schwann cells that express GFAP and surround non- myelinated axons. The enteric nervous system contains a vast population of GFAP-expressing enteric glia that extends throughout the different neural plexuses. Enteric glia surround neuronal cell bodies and axons, as well as contact blood vessels and epithelial cells, and are likely to take part in many gut functions in manners that are similar to astrocytes [32, 202]. GFAP is expressed widely in many tissues by a variety of cell types including mesenchymal stellate cells that share structural and functional similarities with astrocytes in many organs, including liver, kidney, pancreas, lungs, and testes [32, 124, 266]. The functional roles of these cells and their potential similarities with astrocytes are only beginning to be explored, but some appear to share with astrocytes functions in tissue repair and scar formation, as well as newly discovered roles as regulators of local immune and inﬂammatory responses. 123