This is in accord with previous reports that astrocytes infl

This is in accord with previous reports, that astrocytes influence both proliferation and differentiation of embryonic and adult neural stem cells, and specifically promote neurogenic fate of neural stem cells (Roy et al., 2006; Nakayama et al., 2003; Song et al., 2002). Factors that affect neural stem cells range from bone morphogenetic protein (BMPs) (Li et al., 1998), Wnt signaling (Muroyama et al., 2004; Li et al., 2009), to Sonic Hedgehog (Shh) and ciliary neurotrophic factor (CNTF) (Zhu et al., 1999). Not only astrocytes, but also neurons release factors, such as BMPs, that promote neurogenesis from stem cells (Chang et al., 2003). In addition, inhibition of Notch signaling by the γ-secretase inhibitor increases neurogenesis of cultured hESC (Borghese et al., 2010). One cannot, however, exclude the contribution of the regulatory signals provided by cell extracellular matrix (ECM) interaction during this process. Poly-l-ornithine is a non-ECM positively charged polymer, whereas laminin is a component of the ECM which is expressed in the human cortex during developmental stages (Anlar et al., 2002; Flanagan et al., 2006). Laminin/integrin signaling is very important for ECM–cell interactions regulating the fate of neural progenitors (Flanagan et al., 2006; Tate et al., 2004; Ma et al., 2008). Thus, the effect of the entire ECM on the progenitors needs to be taken into account, since they can influence each other and consequently change the final outcome. The finding that co-culturing hESC-RG with the human fetal order XL184 tissue or with conditioned media can accelerate production of specific neuronal subtypes, might have relevance for development of cell-replacement therapies for various neurological disorders from Parkinson\'s, Huntington\'s to Alzheimer\'s disease (Lindvall and Kokaia, 2006, 2009). In Parkinson\'s disease, a progressive loss of dopaminergic (DA) neurons occurs and transplantation of fetal derived DA neurons has shown some promise, but the use of human stem cells has yet to be accomplished (Lindvall and Kokaia, 2006, 2009; Politis and Lindvall, 2012). Particularly, a recent study showed that radial glial cells are the neural progenitors of DA neurons in the human ventral midbrain (Hebsgaard et al., 2009). The following are the supplementary data related to this article
Acknowledgments This study was supported by NIH grant NS041489-10A and Connecticut Stem Cell grants 2008-013 to NZ and 09-SCA-UCHC-13 to SDA. Human fetal tissue was obtained from StemExpress, CA. Patch clamp recordings were performed in the Stem Cell Physiology and Chemistry Core at UConn Health Center, supported by the Connecticut Stem Cell Initiative/Connecticut Innovations grant No. 10-SCD-01. We thank UCHC Stem Cell Core and UCHC FACS facility, Drs J-A Ortega and N Radonjic for help with qPCR, Dr Xiu-Jun Li for valuable suggestions on the manuscript, Nicole Glidden and Greg Wark for technical support and editing.
Introduction Glioblastoma is the most common primary brain tumor in adults and is one of the most deadly and least successfully treated solid tumors (Stupp et al., 2009, 2005). The treatment of this tumor currently involves a combination of surgery, radiotherapy, and chemotherapy (Stupp et al., 2009, 2005; Wen and Kesari, 2008); however, this approach is eventually ineffective, and most patients die within 2years because of tumor recurrence. Therapeutic resistance might occur due to multiple factors, but many recent studies have suggested that a tumorigenic subpopulation of cancer cells, termed cancer stem cells, tumor-initiating cells, or cancer stem-like cells, is highly resistant to radiotherapy and chemotherapy (Bao et al., 2006; Li et al., 2008; Liu et al., 2006; Todaro et al., 2007; Zhang et al., 2008). Glioma stem cells (GSCs), or the so-called glioma-initiating cells, express stem cell markers and have self-renewal capacity, i.e., they have the potential to differentiate into multiple lineages and generate tumors reproducing the characteristics of the original tumor (Park and Rich, 2009). We and others have shown that GSCs contribute to therapeutic resistance, such as resistance to radiotherapy and chemotherapy (Bao et al., 2006; Bleau et al., 2009; Liu et al., 2006; Sato et al., 2011). Current evidence on therapeutic resistance suggests the critical role of GSCs in tumor maintenance and recurrence (Rich and Bao, 2007; Sato et al., 2010). Therefore, novel therapies targeting this subpopulation of cells may significantly improve the outcome of glioblastoma patients (Liu et al., 2006; Zhou et al., 2009).