However, even

with proper oversight, this may in the end be one of the biggest safety hurdles to overcome. In addition to making transplantation of reprogrammed cells affordable and safe, one of the major hurdles thus far left unsolved is to incorporate all of the sequential steps of neuronal differentiation and synaptic development. In particular, forming new projection neurons in the human brain will be a monumental challenge. Consider the case of a Betz cell, which synapses in the lower spinal cord and which is frequently selleck lost in ALS (Udaka et al., 1986). If we were to imagine that the cell body was the size of a tennis ball, the axon would then extend several miles and would be roughly the diameter of

a garden hose. Besides the tens of thousands of dendritic synapses that would find more need to be formed, the axon would need to find its target, starting as a growth cone a considerable distance way. This would all have to transpire within a milieu lacking the guidance cues that are normally present only during a limited window during development. Apart from these practical issues and the host of other intrinsic issues involved in neuronal regeneration and transplantation (accurate cell delivery, potential immune suppression, etc.), there is the growing appreciation that NSCs, whether in vitro or in vivo, have intrinsic specification that may limit the cell types that can be produced upon differentiation (Gaspard et al., 2008, Hochstim et al., 2008, Merkle et al., 2007 and Rakic et al., 2009). Indeed, transplanted hESC-derived neurons seem to obey the in vitro specification program when transplanted in vivo (Gaspard et al., 2008). Beyond this, there was a flurry of findings recently that a small proportion of transplanted cells acquired the pathology of the host tissue (Brundin et al., 2008, Kordower et al., 2008 and Li et al., 2008). Thus, even if we can successfully coax stem cells to replace neurons in vivo, the

battle may already be lost for some of them. Others have taken advantage of the “bystander” or “chaperone” effect of NSCs in transplantation strategies aimed at preventing or ameliorating neurodegeneration (see Breunig et al., 2007 for review). Basically, it has been found that NSCs secrete neurotrophins, MYO10 growth factors, and other beneficial proteins that promote neuronal health and function. For example, it was found that NSCs ameliorated cognitive functions in a model of Alzheimer’s disease not through neuronal replacement but due to their secretion of BDNF (Blurton-Jones et al., 2009). Other groups are taking these properties of transplanted cells and enhancing them with transgenes such as GDNF. In a rat model of ALS, such cells migrated to the sites of degeneration, differentiated into glia, and were able to preserve motor neurons at early and end stages of disease (Klein et al., 2005 and Suzuki et al., 2007).