Neural stem cells as delivery vehicles

The discovery of neural stem cells (NSCs) has changed our long-held view that the adult mammalian central nervous system (CNS) is postmitotic and lacks the capability for self-repair. The role of NSCs in physiological and pathological processes in the brain is slowly emerging. We are now able to isolate, expand, genetically engineer and transplant NSCs. An important characteristic of NSCs, not fully understood so far, is their migratory ability and their tropism to brain pathology. The migratory ability of NSCs and their capacity to differentiate into all neural phenotypes gives us a potentially powerful tool for the treatment of both diffuse and localised neurologic disorders. The delivery of gene products by NSCs to specific sites in the CNS can maximise the efficiency of delivery and minimise the unwanted exposure of surrounding intact tissue. Here, the recent preclinical advances in the use of NSCs for the delivery of therapeutic products are reviewed, in particular the employment of their migratory potential and the homing ability to pathology in the nervous system.     

Neural stem cells as delivery vehicles

The discovery of neural stem cells (NSCs) has changed our long-held view that the adult mammalian central nervous system (CNS) is postmitotic and lacks the capability for self-repair. The role of NSCs in physiological and pathological processes in the brain is slowly emerging. We are now able to isolate, expand, genetically engineer and transplant NSCs. An important characteristic of NSCs, not fully understood so far, is their migratory ability and their tropism to brain pathology. The migratory ability of NSCs and their capacity to differentiate into all neural phenotypes gives us a potentially powerful tool for the treatment of both diffuse and localised neurologic disorders. The delivery of gene products by NSCs to specific sites in the CNS can maximise the efficiency of delivery and minimise the unwanted exposure of surrounding intact tissue. Here, the recent preclinical advances in the use of NSCs for the delivery of therapeutic products are reviewed, in particular the employment of their migratory potential and the homing ability to pathology in the nervous system.     

Overexpression of cdk4 and cyclinD1 triggers greater expansion of neural stem cells in the adult mouse brain

Neural stem cells (NSCs) in the adult mammalian brain generate neurons and glia throughout life. However, the physiological role of adult neurogenesis and the use of NSCs for therapy are highly controversial. One factor hampering the study and manipulation of neurogenesis is that NSCs, like most adult somatic stem cells, are difficult to expand and their switch to differentiation is hard to control. In this study, we show that acute overexpression of the cdk4 (cyclin-dependent kinase 4)-cyclinD1 complex in the adult mouse hippocampus cell-autonomously increases the expansion of neural stem and progenitor cells while inhibiting neurogenesis. Importantly, we developed a system that allows the temporal control of cdk4-cyclinD1 overexpression, which can be used to increase the number of neurons generated from the pool of manipulated precursor cells. Beside providing a proof of principle that expansion versus differentiation of somatic stem cells can be controlled in vivo, our study describes, to the best of our knowledge, the first acute and inducible temporal control of neurogenesis in the mammalian brain, which may be critical for identifying the role of adult neurogenesis, using NSCs for therapy, and, perhaps, extending our findings to other adult somatic stem cells.     

神经干细胞移植治疗研究进展

神经系统起源于胚胎神经管多能干细胞,而成人中枢神经系统内干细胞样前体细胞的发现为应用神经干细胞(NSCs)治疗各种神经系统疾病提供了前提条件。通过内源性NSCs增殖与迁移治疗各种神经元缺失疾病能力有限,而应用NSCs移植或有特定分化潜能的神经前体细胞移植治疗中枢神经系统损伤以及各种神经退行性疾病则可以促进患者神经功能恢复。目前,NSCs疗法所面临的主要问题是如何使NSCs定向分化替代特定功能的神经元,而NSCs疗法研究的热点是如何在分子水平调控NSCs的分化以及损伤区域NSCs的命运。     

Regulatory mechanisms of neural stem cell and strategies for therapy

Neural stem cells(NSCs) are multipotential progenitor cells that can generate neurons, astrocytes, and oligodendrocytes, the three major cell types in the central nervous system. Due to their self-renewal activities, NSCs can proliferate in an undifferentiated state in vitro, allowing them to be expanded mitotically and harvested in bulk. Recent advances in stem cell biology have led us to investigate methods for the regenerative manipulation of the damaged CNS. However, there is much that is still not known about regulatory mechanisms of the differentiation and self-renewal of NSCs. In this article, we review some of the basic notions regarding the extracellular factors and signal transduction cascades involved in the differentiation and maintenance of NSCs.     

Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection

In recent years much excitement has been generated over the possibility that adult stem cells may attempt repair of the injured central nervous system (CNS), thus setting the stage for their utilisation in the treatment of neurodegenerative disorders. Recent studies have shown that some subsets of stem cells can also modulate the (auto)immune response, thus providing a rationale for their use as therapy for experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). This article reviews the scientific evidence supporting the possible use of neural stem cells (NSCs) and mesenchymal stem cells (MSCs) for the treatment of MS. In addition, possible mechanisms sustaining the beneficial mode of action of haematopoietic stem cells (HSCs) following transplantation in MS individuals are discussed. Overall, it is proposed that limited subsets of adult stem cells may have a dual function that may be effective for the treatment of MS, an autoimmune disease of the CNS where degeneration of neural cells follows inflammation.     

The therapeutic potential of adult neural stem cells

Neural stem cells (NSCs) are self-renewing, multipotent cells that generate the neuronal and glial cells of the nervous system. In mammals, contrary to long-held belief, neurogenesis occurs in the adult brain, and NSCs reside in the adult central nervous system. Thus, the brain may be amenable to repair following damage, and new avenues for cell-based therapy are being considered for the treatment of brain disease and injury, such as the stimulation of endogenous progenitor cells, the transplantation of adult-derived neural progenitor and stem cells, and, in particular, autologous cell transplantation. Although significant advances in this field have been made over the past decade, the adult NSC remains an elusive cell for study, and researchers are facing multiple challenges to the development of therapeutic applications from adult NSC research. Among these challenges are the identification and characterization of NSCs in vivo and in vitro, the understanding of the physiology of newly generated neuronal cells in the adult brain, the stimulation of endogenous progenitor cells to promote functional recovery, and the isolation and culture of homogenous populations of neural progenitor or stem cells from the adult brain for cell-based therapy.     

神经干细胞研究进展

本文简要叙述了神经干细胞的发现、研究与脑内移植的前因后果关系。回顾了脑内移植的历史。阐述了神经干细胞的特性、作用及应用前景。神经干细胞可由胚胎干细胞分化而来 ,在人脑中存在 ,可以分离、培养 ,己试用于中枢神经系统的某些退行性疾病 ,前景广阔。但也有不少问题尚未解决 ,离临床普遍开展还有一定的时日。     

Robust In Vivo Transduction of Nervous System and Neural Stem Cells by Early Gestational Intra Amniotic Gene Transfer Using Lentiviral Vector

Presently, in vivo methods to efficiently and broadly transduce all major cell types throughout both the central (CNS) and peripheral adult nervous system (PNS) are lacking. In this study, we hypothesized that during early fetal development neural cell populations, including neural stem cells (NSCs), may be accessible for gene transfer via the open neural groove. To test this hypothesis, we injected lentiviral vectors encoding a green fluorescent protein (GFP) marker gene into the murine amniotic cavity at embryonic day 8. This method (i) efficiently and stably transduced the entire nervous system for at least 80% of the lifespan of the mice, (ii) transduced all major neural cell types, and (iii) transduced adult NSCs of the subventricular zone (SVZ) and subgranular zones (SGZs). This simple approach has broad applications for the study of gene function in nervous system development and adult NSCs and may have future clinical applications for treatment of genetic disorders of the nervous system.     

神经干细胞治疗阿尔茨海默病研究进展

阿尔茨海默病（Alzheimer＇s disease，AD）是中枢神经系统一种常见的进行性神经退行性疾病，是老年前期和老年期痴呆的主要原因。近年来，神经干细胞的发现及体外培养的成功为AD的治疗提供了一个崭新的视野。神经干细胞治疗AD的目的是修复和替代受损神经细胞，重建细胞环路和功能，主要有两种途径，即内源性途径（诱导内源性神经干细胞增殖与分化，使损伤的中枢神经系统进行自我修复）和外源性途径（直接替代缺损组织或植人能分泌促进干细胞增殖与存活的因子的基因工程细胞。一旦神经干细胞的基础研究在细胞增殖、迁移、分化及与宿主融合的机制等制约临床应用的问题方面取得突破，利用神经干细胞治疗AD等引起的脑损伤将会成为现实。     

Neurorestoration in Parkinson's disease by cell replacement and endogenous regeneration

Parkinson's disease (PD) is characterised by a continuous and selective loss of dopaminergic neurons in the substantia nigra pars compacta with a subsequent reduction of the neurotransmitter dopamine. Thus, the prospect of replacing the missing or damaged dopaminergic cells is very attractive. Possible regenerative therapies include transplanting developing neural tissue or neural stem cells into the degenerated host brain and inducing proliferation of endogenous stem cells by pharmacological manipulations. Neural stem cells, with the capacity to self renew and produce the major cell types of the brain, exist in the developing and adult CNS. These cells can be generated and expanded in vitro while retaining the potential to differentiate into nervous tissue. However, one major problem is the control of growth and differentiation of these cells. This review discusses new data on stem cell technology in cell replacement strategies in PD as well as endogenous dopaminergic regeneration.     

Neurorestoration in Parkinson’s disease by cell replacement and endogenous regeneration

Parkinson’s disease (PD) is characterised by a continuous and selective loss of dopaminergic neurons in the substantia nigra pars compacta with a subsequent reduction of the neurotransmitter dopamine. Thus, the prospect of replacing the missing or damaged dopaminergic cells is very attractive. Possible regenerative therapies include transplanting developing neural tissue or neural stem cells into the degenerated host brain and inducing proliferation of endogenous stem cells by pharmacological manipulations. Neural stem cells, with the capacity to self renew and produce the major cell types of the brain, exist in the developing and adult CNS. These cells can be generated and expanded in vitro while retaining the potential to differentiate into nervous tissue. However, one major problem is the control of growth and differentiation of these cells. This review discusses new data on stem cell technology in cell replacement strategies in PD as well as endogenous dopaminergic regeneration.     

Adult neural stem cells and repair of the adult central nervous system

Neural stem cells are present not only in the developing nervous systems, but also in the adult central nervous system of mammals, including humans. The mature central nervous system has been traditionally regarded as an unfavorable environment for the regeneration of damaged axons of mature neurons and the generation of new neurons. In the adult central nervous system, however, newly generated neurons from adult neural stem cells in specific regions exhibit a striking ability to migrate, send out long axonal and dendritic projections, integrate into pre-existing neuronal circuits, and contribute to normal brain functions. Adult stem cells with potential neural capacity recently have been isolated from various neural and nonneural sources. Rapid advances in the stem cell biology have raised exciting possibilities of replacing damaged or lost neurons by activation of endogenous neural stem cells and/or transplantation of in vitro-expanded stem cells and/or their neuronal progeny. Before the full potential of adult stem cells can be realized for regenerative medicine, we need to identify the sources of stem cells, to understand mechanisms regulating their proliferation, fate specification, and, most importantly in the case of neuronal lineages, to characterize their functional properties. Equally important, we need to understand the neural development processes in the normal and diseased adult central nervous system environment, which is quite different from the embryonic central nervous system, where neural development has been traditionally investigated. Here we will review some recent progress of adult neural stem cell research that is applicable to developmental neurobiology and also has potential implications in clinical neuroscience.     

Neurotrophin 3 Transduction Augments Remyelinating and Immunomodulatory Capacity of Neural Stem Cells

Neural stem cells (NSCs) have therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS); however, to date, their use has resulted in only limited clinical and pathological improvement. To enhance their therapeutic capacity, in the present study, we transduced bone marrow–derived NSCs (BM-NSCs) with neurotrophin 3 (NT-3), a potent neurotrophic factor that is both neuroprotective and immunomodulatory. We found that BM-NSCs transduced with NT-3 reduced central nervous system (CNS) inflammation and neurological deficits in ongoing EAE significantly more than conventional NSC therapy, and, in addition, had the following advantages: (i) enhanced BM-NSC proliferation and differentiation into oligodendrocytes and neurons, as well as inhibited differentiation into astrocytes, thus promoting remyelination and neuronal repopulation, and reducing astrogliosis; (ii) enhanced anti-inflammatory capacity of BM-NSCs, thus more effectively suppressing CNS inflammation and accelerating remyelination; (iii) the easy accessibility of BM-NSCs provides another advantage over brain-derived NSCs for MS therapy; and (iv) a novel Tet-on system we used enables efficient control of NT-3 expression. Thus, our study provides a novel approach to break the vicious inflammation-demyelination cycle, and could pave the way to an easily accessible and highly effective therapy for CNS inflammatory demyelination.     

Neurogenesis or non-neurogenesis: that is the question

Neural stem/precursor cells (NPCs) that reside within germinal niches of the adult CNS have more complex roles than previously expected. In addition to their well-documented neurogenic functions, emerging evidence indicates that NPCs exert non-neurogenic functions that contribute to the regulation and preservation of tissue homeostasis under both physiological and pathological conditions. In this issue of the JCI, Mohammad et al. found that DCs efficiently patrol the CNS only when the germinal niche of the subventricular zone functions properly. Indeed, DCs traveled from the ventricles along the rostral migratory stream to the olfactory bulb (a cervical lymph node access point) to dampen anti-CNS immune responses. The authors’ findings further support a non-neurogenic role for NPCs in maintaining tissue homeostasis and promoting tissue protection in the adult brain.     

Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury

The enteric nervous system (ENS) in mammals forms from neural crest cells during embryogenesis and early postnatal life. Nevertheless, multipotent progenitors of the ENS can be identified in the adult intestine using clonal cultures and in vivo transplantation assays. The identity of these neurogenic precursors in the adult gut and their relationship to the embryonic progenitors of the ENS are currently unknown. Using genetic fate mapping, we here demonstrate that mouse neural crest cells marked by SRY box-containing gene 10 (Sox10) generate the neuronal and glial lineages of enteric ganglia. Most neurons originated from progenitors residing in the gut during mid-gestation. Afterward, enteric neurogenesis was reduced, and it ceased between 1 and 3 months of postnatal life. Sox10-expressing cells present in the myenteric plexus of adult mice expressed glial markers, and we found no evidence that these cells participated in neurogenesis under steady-state conditions. However, they retained neurogenic potential, as they were capable of generating neurons with characteristics of enteric neurons in culture. Furthermore, enteric glia gave rise to neurons in vivo in response to chemical injury to the enteric ganglia. Our results indicate that despite the absence of constitutive neurogenesis in the adult gut, enteric glia maintain limited neurogenic potential, which can be activated by tissue dissociation or injury.     

Embryonic stem cells for neural replacement therapy: prospects and challenges

Injury or degeneration of the vertebrate central nervous system often disrupts neuronal circuitry that is built by projection neurons during early embryonic life. Repair of neural network through regeneration of these early-born projection neurons in adult life often fails since stem cells residing in the adult brain are generally programmed to give rise to late-born interneurons. Thus, exogenous cells are needed to rebuild the neural circuitry. Nevertheless, cell replacement in the brain remains a challenging goal because of the lack of safe and effective donor cells, as well as difficulty in remodeling the nonneurogenic adult CNS environment. Here I will concentrate on the donor side and discuss how recent advancement in stem cell technology offers hope for transplant therapy, with a focus on the potentials and hurdles of human embryonic stem cells as a sustainable source.     

神经干细胞在脑外伤中的治疗前景

近年来 ,人们已经证明了发育期和成年哺乳动物的脑中存在着具有未分化性和多潜能性的前体细胞———神经干细胞 ,这些细胞可在体外增殖、克隆和基因操作 ,并可由生长因子诱导分化成某一特定的神经细胞。神经干细胞的这种可塑性特点可用于脑外伤后神经功能缺失的修复与重建的治疗。     

成年神经发生及其在缺血性脑损伤治疗中的应用前景

近年来的研究表明，成年哺乳动物中枢神经系统存在神经干细胞。并且在整个成年期有持续的神经发生。中风能使齿状回颗粒下层和脑室下层的神经发生增加。新产生的神经元能够迁移到损伤区并表达已死亡神经元的标记物。这些研究为脑损伤后的自身修复带来了希望。本文作者主要对成年神经发生和调节以及中风诱导的神经发生和调节进行综述，并进一步探讨中风或其他脑损伤后神经再生的研究方向。     

Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut

It is unclear whether neurogenesis occurs in the adult mammalian enteric nervous system (ENS). Neural crest-derived cells capable of forming multilineage colonies in culture, and neurons and glia upon transplantation into chick embryos, persist throughout adult life in the mammalian ENS. In this study we sought to determine the physiological function of these cells. We discovered that these cells could be identified based on CD49b expression and that they had characteristics of enteric glia, including p75, GFAP, S100B, and SOX10 expression. To test whether new neurons or glia arise in the adult gut under physiological conditions, we marked dividing progenitors with a thymidine analog in rodents under steady-state conditions, or during aging, pregnancy, dietary changes, hyperglycemia, or exercise. We also tested gut injuries including inflammation, irradiation, benzalkonium chloride treatment, partial gut stenosis, and glial ablation. We readily observed neurogenesis in a neurogenic region of the central nervous system, but not reproducibly in the adult ENS. Lineage tracing of glial cells with GFAP-Cre and GFAP-CreERT2 also detected little or no adult ENS neurogenesis. Neurogenesis in the adult gut is therefore very limited under the conditions we studied. In contrast, ENS gliogenesis was readily observed under steady-state conditions and after injury. Adult enteric glia thus have the potential to form neurons and glia in culture but are fated to form mainly glia under physiological conditions and after the injuries we studied.