Transplantation of human neural progenitor cells (NPCs) into the brain or
Transplantation of human neural progenitor cells (NPCs) into the brain or spinal cord to replace lost cells modulate the injury environment or create a permissive milieu to protect and regenerate host neurons is a promising therapeutic strategy for neurological diseases. chopping technique was used to transform adherent iPSCs into free-floating spheres that were easy to maintain and were expandable (EZ spheres) (Ebert et al. 2013 These EZ spheres could be differentiated towards NPC spheres with a spinal cord phenotype using a combination of all-trans retinoic acid (ATRA) and epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) mitogens. Suspension cultures of NPCs derived from human iPSCs or fetal tissue have similar characteristics though they were not similar when grown as adherent cells. In addition iPSC-derived NPCs (iNPCs) survived grafting into the spinal cord of athymic nude rats with no signs of overgrowth and with a very similar profile to human fetal-derived NPCs (fNPCs). These results suggest that human iNPCs behave like fNPCs and could thus be a valuable alternative for cellular regenerative therapies of neurological diseases. Go 6976 INTRODUCTION Fetal neural progenitor cells (fNPCs) can be isolated from different regions of the developing human brain expanded in culture and then differentiated into neurons and glia (Conti and Cattaneo 2010 Kriegstein and Alvarez-Buylla 2009 We have previously shown that fNPCs transplanted into the brain spinal cord or retina in animal models of disease can survive and migrate and provide beneficial effects in some cases (Andres et al. 2011 Nichols et al. 2013 Wang et al. 2008 Moreover we have genetically engineered these cells to produce therapeutic molecules for neuroprotection following transplantation in animal models of Parkinson’s disease and amyotrophic lateral sclerosis (ALS) (Ebert et al. 2008 Suzuki et al. 2007 Other groups have also generated and shown the potential of human fNPCs which in some cases have been taken forward into Federal Drug Administration-approved clinical trials for a number of neurological disorders with no reported serious adverse effects (Azienda Ospedaliera Santa Maria et al. 2012 Glass et al. Go 6976 2012 Neuralstem Inc. and Emory University 2011 ReNeuron Limited 2010 Robberecht and Philips 2013 StemCells 2006 StemCells 2011 StemCells 2012 Tamaki et al. 2002 Taupin 2006 However due to the limited supply concerns of chromosomal aberrations (aneuploidies) during expansion (Sareen et al. 2009 and ethical concerns associated with the use of aborted human fetal tissues there is a pressing need for alternative sources. Human pluripotent stem cells (hPSCs) including embryonic stem cells (ESCs) derived from the blastocyst of a developing embryo and induced PSCs Go 6976 (iPSCs) derived from reprogrammed adult somatic cells have great potential for generating cells for use in regenerative and cell replacement strategies (Okano et al. 2013 Robinton and Daley 2012 Yamanaka 2012 They are essentially immortal allowing limitless cellular expansion and banking and extremely plastic allowing differentiation into any cell type. Human iPSCs also offer an unprecedented opportunity for autologous transplantation possibly circumventing the complexities surrounding immunological rejection with allogeneic human cell transplantation (Araki et al. 2013 Kaneko and Yamanaka 2013 Liu et al. 2013 Okita CASP10 et al. 2011 Zhao et al. Go 6976 2011 Human iPSCs can efficiently develop into neural cells (Chetty et al. 2013 Ebert et Go 6976 al. 2013 Kobayashi et al. 2012 Lee et al. 2012 Zhou et al. 2010 however before iPSC-derived neural cells can be used in clinical transplantation trials they must 1) be shown to be safe 2 maintain a normal cytogenetic status 3 be devoid of residual pluripotent cells to avoid possible malignant tumor formation 4 be reproducibly expanded in large numbers and finally 5) survive and integrate into relevant central nervous system regions. Neuronal replacement is one strategy to use for future clinical transplantation trials. However in fact astroglial cells are the most abundant cell type in the human brain and spinal cord and are now understood to be as important as neurons for brain function (Oberheim et al. Go 6976 2006 They have also been implicated in a number of neurodegenerative diseases with perhaps the best example being ALS where glial dysfunction has been shown to lead to non-cell autonomous death of the motor neurons (Di Giorgio et al. 2007 Haidet-Phillips et al. 2011 Nagai et al. 2007 Yamanaka.