E D ITO R IAL
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 genC 2014 Wiley Periodicals, Inc. V
erated 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
DOI 10.1002/cne.23611 Published online (wileyonlinelibrary.com)
in
Wiley
Online
The Journal of Comparative Neurology | Research in Systems Neuroscience 522:2689–2690 (2014)
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Editorial
autologous tissue in the MPTP primate model of PD. Using cultured cortical biopsy cells from African green monkeys, they demonstrate significant functional recovery and an increase in TH-immunoreactive neurons following striatal transplantation into the same severely dopamine depleted monkeys. Stimulating endogenous neurogenesis to treat PD has several favorable therapeutic advantages compared to neurosurgical intervention with donor stem cells. Offen and colleagues review the neurogenic process in both normal and diseased states in PD patients and animal models of PD, as well as several strategies that utilize mobilization of endogenous neurogenesis for restoration of the nigrostriatal system. Peterson and Bazarek explore the concept of in vivo engineering to facilitate fate conversion of endogenous neural progenitor cells in the cerebral cortex, indicating several of the challenges that will need to be overcome if such an alternative is to be considered a viable therapeutic option in the future Generating preclinical functional data in large animal models of neurodegenerative disorders is imperative toward clinical translation to meet FDA safety and efficacy requirements. Marsala and colleagues review the available pig models of neurological disease and highlight examples of how these models have already been utilized to design a recent phase-1 human clinical trial using cell replacement strategies to treat amyotrophic lateral sclerosis. The reprogramming field has made landmark strides and continues to show promise as a tool to better understand neural development and degeneration. Ang and Wernig review the considerable progress that has been made in the field of induced neural (iN) reprogramming towards defining transcriptional master regulators of lineage fate specification. In just a few years time, this remarkable technique has clearly demonstrated that germ lineage fate conversion can be
2690
achieved in a relatively straightforward manner, however, iN conversion to authentic cell types found in the body (e.g. functional mature neurons) remains elusive. The authors also discuss the current limitations of iN reprogramming that will need to be overcome in order for the novel technique to be applied to disease modeling. The ultimate goal for stem cell-based therapeutics is to provide meaningful long-term functional improvements in diseased patients. Buttery and Barker offer a historical review spanning several decades of cell based therapeutics, gene therapy, and neurosurgical intervention for PD. Using PD as an illustration, they offer critical insight for the stem cell community as a whole that can be applied to a broad array of disorders. Of critical importance, the authors point-out that for any cell based therapeutic to gain widespread clinical acceptance, it must first offer a significant advantage over alternative existing and emerging technologies. The stem cell field has made significant vertical advancements in the past 30 years. The emergence of human pluripotent hESCs by Thompson and colleagues and more recently reprogramming of iPSCs by Yamanaka’s group, and iN cells by Wernig’s group have provided a limitless source of raw material to study how the nervous system is built and how to treat neurological disorders. With the advent of induced neuronal cells, sophisticated new analytical technologies, and increasingly innovative methods that mimic normal human development, creating lineage specific neurons to study and treat disease clinically is at the forefront of our field. We are optimistic for the next decade of stem cell-based research and its future translational potential into the clinic.
The Journal of Comparative Neurology | Research in Systems Neuroscience
Dustin R. Wakeman, Ph.D. Jeffrey H. Kordower, Ph.D.
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 genC 2014 Wiley Periodicals, Inc. V
erated 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
DOI 10.1002/cne.23611 Published online (wileyonlinelibrary.com)
in
Wiley
Online
The Journal of Comparative Neurology | Research in Systems Neuroscience 522:2689–2690 (2014)
Library
2689
Editorial
autologous tissue in the MPTP primate model of PD. Using cultured cortical biopsy cells from African green monkeys, they demonstrate significant functional recovery and an increase in TH-immunoreactive neurons following striatal transplantation into the same severely dopamine depleted monkeys. Stimulating endogenous neurogenesis to treat PD has several favorable therapeutic advantages compared to neurosurgical intervention with donor stem cells. Offen and colleagues review the neurogenic process in both normal and diseased states in PD patients and animal models of PD, as well as several strategies that utilize mobilization of endogenous neurogenesis for restoration of the nigrostriatal system. Peterson and Bazarek explore the concept of in vivo engineering to facilitate fate conversion of endogenous neural progenitor cells in the cerebral cortex, indicating several of the challenges that will need to be overcome if such an alternative is to be considered a viable therapeutic option in the future Generating preclinical functional data in large animal models of neurodegenerative disorders is imperative toward clinical translation to meet FDA safety and efficacy requirements. Marsala and colleagues review the available pig models of neurological disease and highlight examples of how these models have already been utilized to design a recent phase-1 human clinical trial using cell replacement strategies to treat amyotrophic lateral sclerosis. The reprogramming field has made landmark strides and continues to show promise as a tool to better understand neural development and degeneration. Ang and Wernig review the considerable progress that has been made in the field of induced neural (iN) reprogramming towards defining transcriptional master regulators of lineage fate specification. In just a few years time, this remarkable technique has clearly demonstrated that germ lineage fate conversion can be
2690
achieved in a relatively straightforward manner, however, iN conversion to authentic cell types found in the body (e.g. functional mature neurons) remains elusive. The authors also discuss the current limitations of iN reprogramming that will need to be overcome in order for the novel technique to be applied to disease modeling. The ultimate goal for stem cell-based therapeutics is to provide meaningful long-term functional improvements in diseased patients. Buttery and Barker offer a historical review spanning several decades of cell based therapeutics, gene therapy, and neurosurgical intervention for PD. Using PD as an illustration, they offer critical insight for the stem cell community as a whole that can be applied to a broad array of disorders. Of critical importance, the authors point-out that for any cell based therapeutic to gain widespread clinical acceptance, it must first offer a significant advantage over alternative existing and emerging technologies. The stem cell field has made significant vertical advancements in the past 30 years. The emergence of human pluripotent hESCs by Thompson and colleagues and more recently reprogramming of iPSCs by Yamanaka’s group, and iN cells by Wernig’s group have provided a limitless source of raw material to study how the nervous system is built and how to treat neurological disorders. With the advent of induced neuronal cells, sophisticated new analytical technologies, and increasingly innovative methods that mimic normal human development, creating lineage specific neurons to study and treat disease clinically is at the forefront of our field. We are optimistic for the next decade of stem cell-based research and its future translational potential into the clinic.
The Journal of Comparative Neurology | Research in Systems Neuroscience
Dustin R. Wakeman, Ph.D. Jeffrey H. Kordower, Ph.D.
