28 Neuroﬁbromatosis Neuroﬁbromatosis type 1 (NF1) is an inherited neuro- cutaneous disorder with neuropsychologic deﬁcits and predisposition to Schwannomas and astrocytomas caused by mutations in the NF1 gene [2, 9]. Reduced expression of glutamate transporters have been reported in reactive astrocyte clusters in NF1 [263]. Changes in mTOR and PTEN-signaling pathways in Schwann cells and astrocytes may contribute to tumorigenesis in NF1 [50, 87]. Enteric glia and inﬂammatory bowel disorders The gastrointestinal tract is highly innervated and neuro- pathology of the enteric nervous system is emerging as a central feature of many gut diseases. Although most considerations of the enteric nervous system have focused on neuronal dysfunction, a large population of astrocyte- like glia populates gut muscle layers and the intestinal mucosa, and mounting new evidence points toward enteric glia, which express GFAP and share functional similarities with astrocytes, as active participants in gut pathology [207]. Various lines of experimental and neuro- pathological evidence are consistent with the possibility that enteric glia constitute a previously unrecognized disease target in pathologies associated with intestinal barrier dysfunction, notably inﬂammatory bowel disease, necrotizing enterocolitis, irritable bowel syndrome, diabe- tes, autoimmune disease, and neurotropic virus infection of the gut pathology [44, 207]. Experimental ablation of enteric glia leads to inﬂammatory bowel disease [32]. Both astrocytes and related enteric glial cells are able to induce barrier properties in gut epithelial cells, and S-nitrosoglutathione (GSNO) has been identiﬁed as one molecular mediator of this effect [208]. Thus, enteric glia, like astrocytes, appear to play essential roles in barrier functions during disease processes, particularly as regards regulating the spread of inﬂammation [49, 207, 226, 251]. GFAP-expressing stellate cells within liver, pancreas, and kidney There is now growing evidence that stellate shaped, GFAP-expressing cells in various tissues may have functions that are similar to those of astrocytes. For example, there is increasing evidence that GFAP- expressing pancreatic stellate cells play important roles in tissue repair, ﬁbrosis, and scar formation [176]. Hepatic stellate cells not only express GFAP and have morphological appearance similar to astrocytes, but also contact hepatic sinusoids and blood vessels and may take part in hepatic immune processes [258, 259]. In this 123 Acta Neuropathol (2010) 119:7–35 regard, it is particularly interesting that the liver, like the CNS, has a certain level of immune privilege [241], and that both CNS and liver have resident populations of macrophage-related cells (Kupfer cells in the liver and microglia in the CNS) as well as of stellate cells that participate in immune and inﬂammatory processes. In addition, there is evidence that GFAP-expressing mesangial cells in the kidney function as local modula- tors of innate and adaptive immune responses [209]. The increasing recognition that tissue-speciﬁc cells like astrocytes and stellate cells play essential roles in regu- lating local immune and inﬂammatory processes is likely to impact considerably on concepts about organ-speciﬁc vulnerability to autoimmunity and other inﬂammatory conditions. Therapeutic strategies involving astrocytes The actively ongoing dissection of molecular mechanisms of reactive astrogliosis is beginning to identify molecules whose functions might be enhanced or blocked in speciﬁc disease contexts as potential therapeutic strategies [66, 226]. For example, augmenting the function of the astro- cyte glutamate transporter EAAT2 with parawexin 1, a molecule isolated from spider venom, protects retinal neurons from ischemic degeneration by enhancing gluta- mate uptake and reducing excitotoxicity [70]. Certain b-lactam antibiotics, identiﬁed by a high-throughput screen of small molecules, can stimulate the expression of astrocyte glutamate transporters sufﬁciently to reduce excitotoxicity and neuroprotection in models of stroke and ALS [199]. Transplantation strategies involving astrocytes are also under investigation. For example, grafts of stem or pro- genitor cells that mature into healthy astrocytes cells are reported to improve outcome in a mouse model of ALS in which host astrocytes are abnormal and express a mutant SOD [120]. A different strategy employs grafts of astro- cytes that are genetically modiﬁed to produce speciﬁc molecules, such as growth factors, as therapeutic pumps to deliver those molecules in speciﬁc locations [18, 233]. In due course, grafted astrocytes may be tested in clinical contexts and become subject to neuropathological evaluations. Acknowledgments Work in the authors’ laboratories is supported by grants from NIH, RO1 NS057624 (MVS), P50 AG16570 (HVV) and P01 AG12435 (HVV), the Roman Reed Spinal Cord Injury Research Fund (MVS) and Wings for Life (MVS) and the Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine (HVV). Nicole Yin and Spencer Tung assisted with preparation of illustrations. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which