oa Editorial [Hot Topic: Advances and Perspectives on Stem Cell Therapy for Human Neurodegenerative Diseases (Guest Editor: Liang-Wei Chen)]

Human neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD) result from progressive death of specific populations of CNS neurons, and represent a fast growing health challenge. Current therapeutics relieve disease symptoms, but fail to halt disease progression or cure these deliberating diseases. Stem cell strategies hold strong promise for human neurodegenerative diseases, which may be achieved by transplantation of stem cells and manipulation of neurogenesis processing. While natural neurogenesis declines markedly with aging and the low efficiency of new neural cell generation limits its regenerative capability [1], multipotent stem cells, i.e. embryonic stem (ES) cells, are capable of inducing pluripotent stem cells and mesenchymal stem cells and represent a promising source for cell replacement therapy due to their ability to generate various types of functional neural cells [2-4]. Many critical questions regarding basic stem cell biology, mechanisms, development, reprogramming, and clinical safety (for example, concern over the tumorigenicity of pluripotent stem cells) of their transplantation still remain, and should be properly addressed before the translational applications in the treatment of human neurodegenerative diseases [4-6]. Even so, successful translational clinical trials utilizing stem cell therapy are already coming to light,.and new cell replacement strategies based on advanced stem cell technology and translational application will hopefully overcome these incurable human neurodegenerative diseases in future regenerative medicine [5, 6]. This special issue presents a collection of comprehensive reviews to highlight the neural induction and patterning, cell reprogramming, molecular targeting regulation for specific neuronal differentiation, neural repair or regeneration, and stem cell transplant applications to the neurodegenerative diseases. This special issue begins with Fumitaka Osakada and Masayo Takahashi reviewing the neural induction and patterning in mammalian pluripotent stem cells. The acquisition of neural fates in ES cells can be controlled by bone morphogenetic protein, fibroblast growth factor, and Wnt signaling, while the production of specific neural cell types can also be regulated by exogenous patterning signals such as Wnt, bone morphogenetic protein, sonic hedgehog protein, fibroblast growth factor, and retinoic acid. Spatiotemporal neural patterning of ES cells in embryogenesis and in in vitro neural differentiation in response to these signals are reviewed. Oscar Arias-Carrion follows with a discussion of adult neurogenesis in the hypothalamus and its possible functions and implications. Adult neurogenesis occurs actively in the dentate gyrus of hippocampus and the subventricular zone in a constitutive manner under physiological conditions. The author presents recent evidence of low proliferative neurogenesis in the hypothalamus and points out the potential contribution of these new neurons to neural processing, suggesting that the hypothalamus may serve as a new source and target for stem cell transplantation. Jeremy M. Crook reviews human embryonic stem cell therapies for neurodegenerative diseases. The author discusses putative clinicallycompliant strategies for human ES cell maintenance and directed differentiation, greater understanding and accessibility to cells through formal cell registries and centralized cell banking for distribution, and the revised US government policy on funding human ES cell research. Considering the practical and fiscal constraints of delivering cell therapies for global healthcare, a more efficient and economical application will bolster the clinical entry of human ES cell derivatives. Advances and challenges of translating human ES cells into novel therapies for neurodegenerative diseases are summarized, with the suggestion that PD be considered as a primary candidate for human ES cell therapy. L.W. Chen and colleagues review the potential application of induced pluripotent stem (iPS) cells in cell replacement therapy for PD. While the difficulty in securing donor dopamine neurons and immuno-rejection of neural transplants hinder application of ES cells, iPS cells offers a new source for cell replacement therapies in human neurodegenerative diseases. This review summarizes current methods and modifications in producing iPS cells from somatic cells, safety concerns of reprogramming procedures, and animal studies for testing the therapeutic value of iPS cells in the treatment of PD. Patient-specific iPS cells and efficient inducement of dopamine neurons may further benefit diseasespecific screening and personalized stem cell therapy for human PD. Omar M.E. Abdel-Salam contributes a review on stem cell therapy for human AD. There is evidence for inefficient adult neurogenesis in the pathogenesis of AD, and grafted stem cells can survive, migrate, and differentiate into cholinergic neurons, astrocytes, and oligodendrocytes, with amelioration of learning and memory deficits. In addition to replacement of lost or damaged cells, grafted stem cells might stimulate endogenous neural precursors and enhance neuroplasticity. Furthermore, antidepressant drugs, lithium, acetyl cholinesterase inhibitors and ginkgo biloba enhance the impaired neurogenesis in this disease process. This review points out that pharmacological manipulation of neurogenesis may offer an alternative approach in combination with stem cell therapy for human AD. Yvona Mazurova reviews interventions of proliferation and differentiation of endogenous neural stem cells in the neurodegenerative process of HD phenotype. HD is characterized by degeneration of a relatively well-defined neuronal cell population in the caudate nucleus, which is adjacent to the neurogenic subependymal zone (SEZ) region. The possibility to harness endogenous neural stem cell capacity for repair by promoting SEZ neurogenesis paves the way for a new clinical management of this disorder. This article points out characterization of the neurogenic niche of SEZ in reaction to brain injury and HD disease process, showing new insights into potential application of SEZ neurogenesis, migration of progenitor cells, and generation of new neurons in the treatment of human HD. Daisy K.Y. Shum and Y.S Chan contribute a comprehensive review on derivation of clinically applicable Schwann cells from bone marrow stromal cells for neural repair and regeneration. Schwann cells are critically important for neural repair, axonal regrowth and remyelination in peripheral nerve lesions. The absence of Schwann cells in the CNS limits the regenerative capacity of central neurons. The authors have expertise in the development of Schwann cell phenotype from mesenchymal stem cells (MSCs), and discuss methods for derivation of Schwann cell-like cells from MSCs, issues related to instability of the derived Schwann cell phenotype, apoptosis of derived cells in transplants, and the inability to predict with confidence how the cells will behave after transplantation. They suggest that further elucidation of biological signaling by Schwann cells derived from MSCs will promote establishing a new therapeutic strategy based on Schwann cell properties for CNS injury and/or neurodegenerative diseases. Q.Y. Xu and J.P. Zhao review possible restorative treatment for PD by inducement of dopamine neurons from adult stem cells. Recent progress in adult stem cell studies indicate that functional neurons derived from adult tissue stem cells may expand stem cell therapy application for neurodegenerative diseases. The authors summarize various types of adult tissue stem cells, basic biological properties, and differentiation inducement of dopaminergic neuronal cells. They point out that using adult stem cells should overcome the ethical problem of human fetal tissue or ES cells, and open the possibility of patient-specific autologous transplantation and personalized treatment for PD. Y.X. Ding, X Wang and colleagues close this issue with a discussion of molecular manipulation targeting dopamine phenotype differentiation of stem cells. Focusing on understanding the differentiation mechanism and controlled proliferation of stem cells, they present advances on candidate signaling molecules and transcription factors in potential regulation processes of dopamine differentiation and proliferation of stem cells, with emphasis on Wnt/β-catenin, Notch, sonic hedgehog signaling, and several dopaminergic cell fate-related transcription factors. Additionally, activation of oncogenes in abnormal cell proliferation or tumorigenicity of pluripotent stem cells are also discussed. It suggested that selective molecular targeting interventions will greatly benefit stem cell therapy for human PD. ACKNOWLEDGEMENTS L.-W. Chen is supported by grants from the National Science Basic Research Program of China (No. 2011CB504103) and National Natural Science Foundation (Nos. 30772279, 30970862 and 81071609). The Guest Editor would like to thank all authors for their comprehensive review contributions to this special issue, and also Ms. H. Wahaj and Editor-in-Chief Dr. S.D. Skaper for their excellent coordination of this special issue of CNS & Neurological Disorders-Drug Targets.