Special issue on stem cells

The advancement of techniques to derive stem cells from adult tissue and pluripotent sources including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have greatly influenced not only our ability to model and investigate complex mechanisms of disease, but have also opened a new era for cell replacement therapies in a variety of neurodegenerative disorders. The authors of this special issue of the Journal of Comparative Neurology were invited based on their expertise and significant contributions toward the advancement of the field. This special issue features a variety of original articles focusing on the derivation and characterization of multipotent neural stem cells (NSCs) and differentiated neurons derived from ESCs and iPSCs. Anderson and colleagues demonstrate a methodology to derive karyotypically normal NSCs from human ESCs and iPSCs under xeno-free/feeder-free conditions, utilizing growth factors and attachment substrate to enhance the oligodendrocytic lineage and achieve tripotency. The Svendsen’s laboratory describes a new technique utilizing a novel sphere-chopping method in combination with retinoic acid and mitogens to derive a limitless source of NSCs from human iPSCs. These iPSC derived NSCs shared similar characteristics to fetally derived NSCs both in vitro and in vivo when grafted into the spinal cord of athymic nude rats, providing an alternative renewable substrate to fetal tissue sources. In order to enhance neurite outgrowth from human ESC derived NSCs in vitro, Keirstead’s group utilizes pharmacological inhibition of PTEN to enhance PI3K/Akt signaling. In addition, they demonstrate PTEN inhibition can rescue outgrowth when exposed to a myelin inhibitory substrate in a microfluidic co-culture assay, indicating a possible therapeutic treatment to enhance endogenous fiber outgrowth following CNS injury. Pluripotent stem cells have become a highly valuable tool to investigate corticogenesis and examine neural defects during early development. Sadegh and Macklis, employ a standardized, partially directed monolayer differentiation protocol to derive a heterogeneous population of neocortical-like neurons from mouse ESCs. Of considerable interest, they utilize an array of positive and negative forebrain markers to demonstrate that these neurons are stalled as distinct immature subtypes compared to primary developmentally matched neocortical neurons in vivo. These results highlight the differences between cortical neurons generated in vitro vs. in vivo, including incorrectly specified progenitor cells, indicating that a refinement of lineage directed methodologies will be of great clinical importance for future translation. The Brustle’s laboratory reviews fundamental neurodevelopmental principles and their application to pluripotent stem cell culture. They examine early cortical neurogenesis and recent advances that have been made in generating subtype specific cortical neurons from both ESCs and iPSCs. Utilizing 2D or 3D culturing systems, the authors demonstrate the derivation of stage specific progenitors from 2D rosettes, as well as suspension 3D culture of “cerebral organoids” as a means to model early corticogenesis as well as investigate neurodevelopmental defects. They also focus on the development of retinal “optic cups” demonstrating their ability to recapitulate complex morphogenetic processes in vitro. A greater understanding of how environmental and genetic factors affect neurogenesis in normal and diseased states is critical to developing new therapies for neurological disorders. A fascinating study by Gage and colleagues explores the interaction of environment on modulation of hippocampal neurogenesis. They demonstrate that mushroom spine morphogenesis and integration of newborn hippocampal granule cells is differentially regulated by experience. Alterations in spatial and non-spatial complexity resulted in changes in distinct dendritic segments of the outer or middle molecular layer of the dentate gyrus. The Lipton’s laboratory review’s the potential for utilizing human ESC derived neural precursor cells as a cellular source for treatment of Parkinson’s disease (PD). They examine the state-of-the-art techniques for derivation of midbrain lineage, A9 dopamine neurons from pluripotent cells and consider the potential role for genetic programming with MEF2C as a means to address some of the key hurdles remaining towards clinical translation. Importantly, they highlight several key issues encountered in past clinical trials involving fetal tissue including patient selection, trial design, and surgical aspects that will be important for translational success with pluripotent cell sources in the future. Harnessing endogenous precursor cells for treatment of neurodegenerative disorders continues to be an area of great interest to the stem cell field. Work from Bloch and Redmond’s groups explore autotransplantation of