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  • br Acknowledgments br This work was supported by the Nationa

    2018-11-08


    Acknowledgments
    This work was supported by the National Institutes of Health grant 5UO01DK089569-05 (Beta Cell Biology Consortium/M.G.) and The Leona M. and Harry B. Helmsley Charitable Trust grant 2012PG-T1D010 (M.G.)
    Introduction Astrocytes are the most abundant cell type in the human brain. They play a critical role in the maintenance of homeostasis of the central nervous system (CNS) by a wide spectrum of functions. These functions include, but are not restricted to, regulation of blood flow (Attwell et al., 2010), regulation of energy reserves (Choi et al., 2012), modulation of synaptic transmission (Simard and Nedergaard, 2004), neuronal connectivity (Eroglu and Barres, 2010), and uptake of potentially pathogenic proteins (Lee et al., 2010; Wakabayashi et al., 2000). Furthermore, astrocytes can be triggered by environmental cues including cytokines and chemokines to become reactive during brain injury (Chen and Swanson, 2003) and neurodegenerative diseases, such as amyotrophic lateral sclerosis (Haidet-Phillips et al., 2011; Yamanaka et al., 2008) and Parkinson\'s disease (Waak et al., 2009). Although these reactive astrocytes are thought to have a neuroprotective function, astrocyte reactivity has also been associated with neurotoxicity (Chao et al., 1996; Episcopo et al., 2013; Lee et al., 2013; Pekny et al., 2014); the mechanisms of balance between neuroprotection and neurotoxicity are still not well understood. During human brain development, neuroepithelial cells are subject to regional patterning through the effects of morphogens such as retinoic tryptophan hydroxylase (RA) or sonic hedgehog (SHH) (Kiecker and Lumsden, 2012; Rowitch and Kriegstein, 2010). Neuroepithelial cells have the potential to differentiate into glial cell types (astrocytes and oligodendrocytes) and distinct neuronal subtypes characterized by the neurotransmitter they release and expression of regional identity markers. Recent work has evidenced that positional diversity also exists among astrocytes (Tsai et al., 2012), therefore raising a growing interest in the effects of patterning factors during the development of astrocytes. Moreover, there is increasing evidence that astrocytes may differ between brain structures, and within these structures, depending on their location along the dorso-ventral and rostro-caudal axis (Anderson et al., 2014; Bachoo et al., 2004; Chaboub and Deneen, 2012). Because primary human material is not always accessible, advance in the understanding of astrocyte development and diversity has mainly been based on observations in rodent models (Deneen et al., 2006; Hochstim et al., 2008), and it is only recently that investigations using human astrocytes have been made to better characterize their functional properties, in vivo (Han et al., 2013; Oberheim et al., 2009). One of the few feasible sources to investigate human astrocyte development and function in health and disease is via human pluripotent stem cells (PSCs). Human PSCs include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) which often are the primary source of material used to study neuronal subtypes in vitro using protocols that include time-specific exposure to patterning cues following developmental principles (Hu et al., 2010; Swistowski et al., 2010). Recently, different protocols have also been described for the differentiation of human PSCs into regionalized astrocytes in vitro (Jiang et al., 2013; Juopperi et al., 2012; Kondo et al., 2013; Krencik et al., 2011; Roybon et al., 2013; Serio et al., 2013; Shaltouki et al., 2013; Yuan et al., 2011). However, as opposed to the multitude developed for generating spinal cord astrocytes (Jiang et al., 2013; Krencik et al., 2011; Roybon et al., 2013; Serio et al., 2013), only few exist for generating forebrain and midbrain astrocytes (Juopperi et al., 2012; Kondo et al., 2013; Krencik et al., 2011). The efficiency of these protocols to generate astrocytes, however, varies greatly not only depending on the type of PSCs primarily used, but also in-between individual iPSC lines generated from one or multiple patients. With PSC technologies potential to personalize medical therapy in the near future, there is a need for tools that can provide a reliable source of homogenous astrocyte populations, regardless of the primary material, enabling development of cellular models for the study of astrocytes maintenance of brain homeostasis in health and disease.