In conclusion our experimental setting allowed

In conclusion, our experimental setting allowed the identification of differences in survival and proliferation pathways between PN and MES GSCs. The sensitivity of MES GSCs to the silencing of AXL highlights its importance in this subgroup of GSCs and suggests its potential for use as a therapeutic target.
Experimental Procedures
Author Contributions
Acknowledgments
Introduction With the first reports on generating human induced pluripotent stem cmv (hiPSCs) from human cells (Takahashi et al., 2007; Yu et al., 2007), the controversy regarding the ethics of research involving human embryonic stem cells (hESCs) (Thomson et al., 1998) has arisen once again (Holm, 2008). Opponents of hESC research have been quick to argue that, considering the availability of an alternative source of human PSCs (hPSCs), research in hESCs is no longer needed to realize the promise of hPSCs. However, even before the derivation of hiPSCs was first reported, leading scientists in the field of hPSC research emphasized the need to continue research in ESCs in case hiPSCs became available (Hyun et al., 2007). Several arguments have been put forward to support the continuation or even an extension of hESC research. For example, it has been reasoned that hESCs have advantages over hiPSCs for regenerative therapies because the latter may contain somatic mutations or reprogramming-induced epigenetic defects. Indeed, there are currently 11 clinical trials registered with the FDA in which hESC-derived cells are being used, mainly to establish treatments for different forms of macular degeneration, but also for neurological, cardiac, and pancreatic disorders (NIH, clinicaltrials.gov; https://clinicaltrials.gov/). Although the first results from one of the studies on macular degeneration have been reported (Schwartz et al., 2015), the vast majority of these trials started very recently, at a time when hiPSCs have already been available for years. Currently, hiPSC-derived cells are being used in one clinical trial in Japan (UMIN Clinical Trial Registry, ID UMIN000011929; http://www.umin.ac.jp/ctr/). Another argument in favor of continuing the use of hESCs is their utility for basic research (e.g., to gain a better understanding of human ground-state pluripotency) (Gafni et al., 2013), for studies of early human development (Niakan et al., 2012), or as cells that are unimpeded by epigenetic or environmental disturbances that are likely present in hiPSCs (e.g., to study gene function in a rather naive cell). One of the most widely used arguments to justify hESC research is that these cells are still needed as the “gold standard” for human pluripotency to characterize and qualify hiPSC lines and gain a deeper understanding of the reprogramming process. This argument is frequently used in the political debate among stem cell researchers and proponents of hESC research, and has become a central point in the attempt to justify continued support for this research, for example, by the European Union. Thinking this argument through implies that research into hESCs would mainly lead to a more complete understanding of induced pluripotency and would become more and more dispensable with increasing progress in hiPSC research. Indeed, although novel and less invasive methods for reprogramming somatic cells to pluripotency have been developed in recent years, and some difficulties in the reprogramming procedure have been overcome (Anokye-Danso et al., 2011; Kim et al., 2009; Warren et al., 2010; Yoshioka et al., 2013; Yu et al., 2009), many controversial studies have reported differences between the two types of hPSCs on both genetic and epigenetic levels (Liang and Zhang, 2013; Ma et al., 2014) that may, for example, result in deviant behaviors in specific differentiation settings (Bar-Nur et al., 2011; Hu et al., 2010; Mills et al., 2013). Thus, it is currently unequivocally crucial to use hESCs as a reference material to gain a deeper understanding of hiPSC biology and to improve reprogramming strategies.