对比不同类型干细胞对于缺血性脑卒中治疗的研究进展

成人中枢神经系统存在着一定量的神经干细胞,其具有两大关键能力;自我更新和多向分化潜能。缺血性脑卒中是一种由于由脑血流的缺失或减少引起的脑动脉闭塞,进而导致脑组织梗死的脑血管疾病。虽然对于脑损伤的药物治疗已经取得了一定的成果,但目前以干细胞为基础的治疗方法仍成为了研究热点。无论是内源性神经干细胞还是外源性神经干细胞移植均可在脑损伤后向远端损伤区迁移并分化成新的神经细胞,从而在中枢神经系统疾病尤其是脑梗死后进行组织修复和功能恢复。因此在这篇综述中,我们主要探讨不同类型的干细胞对脑梗死介导的脑损伤的应用潜能,对比不同类型干细胞对缺血性脑卒中的治疗优缺点。     

Regeneration of the central nervous system using endogenous repair mechanisms

Recent advances in developmental and stem cell biology have made regeneration-based therapies feasible as therapeutic strategies for patients with damaged central nervous systems (CNSs), including those with spinal cord injuries, Parkinson disease, or stroke. These strategies can be classified into two approaches: (i) the replenishment of lost neural cells and (ii) the induction of axonal regeneration. The first approach includes the activation of endogenous neural stem cells (NSCs) in the adult CNS and cell transplantation therapy. Endogenous NSCs have been shown to give rise to new neurons after insults, including ischemia, have been sustained; this form of neurogenesis followed by the migration and functional maturation of neuronal cells, as well as the responses of glial cells and the vascular system play crucial roles in endogenous repair mechanisms in damaged CNS tissue. In this review, we will summarize the recent advances in regeneration-based therapeutic approaches using endogenous NSCs, including the results of our own collaborative groups.     

Neural stem cells as biological minipumps: a faster route to cell therapy for the CNS?

One strategy for the use of neural stem cells (NSCs) in treating neurological disorders is as transplantable "biological minipumps", in which genetically engineered neural stem cells serve as sources of secreted therapeutic (neuroprotective or tumoricidal) agents. Neural stem cells are highly mobile within the brain and demonstrate a tropism for various types of central nervous system (CNS) pathology, making them promising candidates for targeted gene delivery vehicles. Although neural stem cells have also been proposed as a potential source of replacement neurons and astrocytes to repopulate injured or degenerating neural circuits, the challenges involved in rebuilding damaged brain architecture are substantial and remain an active area of investigation. In contrast, the use of NSCs as biological minipumps does not rely on neuronal differentiation, axonal targeting, or synaptogenesis. This strategy may be a faster route to cell-based therapy of the CNS and is poised to move into human clinical trials. This review considers two types of neurologic disease that may be suitable targets for this alternative approach to NSC therapy: glial brain tumors and traumatic brain injury. We examine some of the key scientific and technical issues that must be addressed for the successful use of NSCs as minipumps.     

Regulatory genes controlling cell fate choice in embryonic and adult neural stem cells

Neural stem cells are the most immature progenitor cells in the nervous system and are defined by their ability to self-renew by symmetric division as well as to give rise to more mature progenitors of all neural lineages by asymmetric division (multipotentiality). The interest in neural stem cells has been growing in the past few years following the demonstration of their presence also in the adult nervous system of several mammals, including humans. This observation implies that the brain, once thought to be entirely post-mitotic, must have at least a limited capacity for self-renewal. This raises the possibility that the adult nervous system may still have the necessary plasticity to undergo repair of inborn defects and acquired injuries, if ways can be found to exploit the potential of neural stem cells (either endogenous or derived from other sources) to replace damaged or defective cells. A full understanding of the molecular mechanisms regulating generation and maintenance of neural stem cells, their choice between different differentiation programmes and their migration properties is essential if these cells are to be used for therapeutic applications. Here, we summarize what is currently known of the genes and the signalling pathways involved in these mechanisms.     

Human stem cells for CNS repair

Although most peripheral tissues have at least a limited ability for self-repair, the central nervous system (CNS) has long been known to be relatively resistant to regeneration. Small numbers of stem cells have been found in the adult brain but do not appear to be able to affect any significant recovery following disease or insult. In the last few decades, the idea of being able to repair the brain by introducing new cells to repair damaged areas has become an accepted potential treatment for neurodegenerative diseases. This review focuses on the suitability of various human stem cell sources for such treatments of both slowly progressing conditions, such as Parkinson’s disease, Huntington’s disease and multiple sclerosis, and acute insult, such as stroke and spinal cord injury. Despite stem cell transplantation having now moved a step closer to the clinic with the first trials of autologous mesenchymal stem cells, the effects shown are moderate and are not yet at the stage of development that can fulfil the hopes that have been placed on stem cells as a means to replace degenerating cells in the CNS. Success will depend on careful investigation in experimental models to enable us to understand not just the practicalities of stem cell use, but also the underlying biological principles.     

Neurogenesis in the adult central nervous system

Contrary to the long-held dogma, neurogenesis occurs throughout adulthood, and neural stem cells reside in the adult central nervous system (CNS) in mammals. The developmental process of the brain may thus never end, and the brain may be amenable to repair. Neurogenesis is modulated in a wide variety of physiological and pathological conditions, and is involved in processes such as learning and memory and depression. However, the relative contribution of newly generated neuronal cells to these processes, as well as to CNS plasticity, remains to be determined. Thus, not only neurogenesis contributes to reshaping the adult brain, it will ultimately lead us to redefine our knowledge and understanding of the nervous system.     

极小胚胎样干细胞与神经再生

再生医学的目的是为了减轻组织损伤所致的不可逆性功能损害,多种类型的干细胞可促进神经再生,发挥治疗作用。近来,在骨髓和其他组织中发现了一种数量极少的极小胚胎样干细胞(VSELs),其分子标志为Oct-4+CXCR4+SSEA-1+Sca-1+lin-CD45-,它们可动员到外周血中。在给予动员剂或组织损伤等应激情况下可向损伤区迁移,现在认为它是高度迁移的外胚层/生殖系源性的干细胞群,具有多能干细胞特征,能分化为三个胚层细胞,综上所述,极小胚胎样干细胞可能通过促进神经再生修复中枢神经系统损伤。     

Neural stem cells: involvement in adult neurogenesis and CNS repair

Recent advances in stem cell research, including the selective expansion of neural stem cells (NSCs) in vitro, the induction of particular neural cells from embryonic stem cells in vitro, the identification of NSCs or NSC-like cells in the adult brain and the detection of neurogenesis in the adult brain (adult neurogenesis), have laid the groundwork for the development of novel therapies aimed at inducing regeneration in the damaged central nervous system (CNS). There are two major strategies for inducing regeneration in the damaged CNS: (i) activation of the endogenous regenerative capacity and (ii) cell transplantation therapy. In this review, we summarize the recent findings from our group and others on NSCs, with respect to their role in insult-induced neurogenesis (activation of adult NSCs, proliferation of transit-amplifying cells, migration of neuroblasts and survival and maturation of the newborn neurons), and implications for therapeutic interventions, together with tactics for using cell transplantation therapy to treat the damaged CNS.     

The culture of neural stem cells

A stem cell has three important features. Firstly, the ability of self‐renewal: making identical copies of itself. Secondly, multipotency, generating all the major cell lineages of the host tissue (in the case of embryonic stem cells—pluripotency). Thirdly, the ability to generate/regenerate tissues. Thus, the study of stem cells will help unravel the complexity of tissue development and organisation, and will also have important clinical applications. Neural stem cells (NSCs) are present during embryonic development and in certain regions of the adult central nervous system (CNS). Mobilizing adult NSCs to promote repair of injured or diseased CNS is a promising approach. Since NSCs may give rise to brain tumor, they represent in vitro models for anti‐cancer drug screening. To facilitate the use of NSCs in clinical scenarios, we need to explore the biology of these cells in greater details. One clear goal is to be able to definitively identify and purify NSCs. The neurosphere‐forming assay is robust and reflects the behavior of NSCs. Clonal analysis where single cells give rise to neurospheres need to be used to follow the self‐renewal and multipotency characteristics of NSCs. Neurosphere formation in combination with other markers of NSC behavior such as active Notch signaling represents the state of the art to follow these cells. Many issues connected with NSC biology need to be explored to provide a platform for clinical applications. Important future directions that are highlighted in this review are; identification of markers for NSCs, the use of NSCs in high‐throughput screens and the modelling of the central nervous development. There is no doubt that the study of NSCs is crucial if we are to tackle the diseases of the CNS such as Parkinson's and Alzheimer's. J. Cell. Biochem. 106: 1–6, 2009. © 2008 Wiley‐Liss, Inc.     

脐带血来源干细胞神经分化的研究进展

中枢神经系统损伤后的自身修复能力有限,因而研究者致力于寻找一种合适的细胞进行移植以代替受损的神经细胞修复神经损伤。近年来的研究表明,脐带血干细胞能够在体外诱导条件下向神经样细胞分化,并在动物体内实验中促进神经损伤的恢复,有可能作为一种有效的细胞资源,应用于人类中枢神经系统疾病的细胞替代治疗以及神经保护与支持。     

Cell replacement therapies for nervous system regeneration

The adult brain was thought to be a slowly decaying organ, a sophisticated but flawed machine condemned to inevitable decline. Today we know that the brain is more plastic than previously assumed, as most prominently demonstrated by the constitutive birth of new neurons that occurs in selected regions of the adult brain, even in humans. However, the overall modest capacity for endogenous repair of the central nervous system (CNS) has sparked interest in understanding the barriers to neuronal regeneration and in developing novel approaches to enable neuronal and circuit repair for therapeutic benefit in neurodegenerative disorders and traumatic injuries. Scientists recently assembled in Baeza, a picturesque town in the south of Spain, to discuss aspects of CNS regeneration. The picture that emerged shows how an integrated view of developmental and adult neurogenesis may inform the manipulation of neural progenitors, differentiated cells, and pluripotent stem cells for therapeutic benefit and foster new understanding of the inner limits of brain plasticity.     

Growing Neural Stem Cells from Conventional and Nonconventional Regions of the Adult Rodent Brain

Recent work demonstrates that central nervous system (CNS) regeneration and tumorigenesis involves populations of stem cells (SCs) resident within the adult brain. However, the mechanisms these normally quiescent cells employ to ensure proper functioning of neural networks, as well as their role in recovery from injury and mitigation of neurodegenerative processes are little understood. These cells reside in regions referred to as "niches" that provide a sustaining environment involving modulatory signals from both the vascular and immune systems. The isolation, maintenance, and differentiation of CNS SCs under defined culture conditions which exclude unknown factors, makes them accessible to treatment by pharmacological or genetic means, thus providing insight into their in vivo behavior. Here we offer detailed information on the methods for generating cultures of CNS SCs from distinct regions of the adult brain and approaches to assess their differentiation potential into neurons, astrocytes, and oligodendrocytes in vitro. This technique yields a homogeneous cell population as a monolayer culture that can be visualized to study individual SCs and their progeny. Furthermore, it can be applied across different animal model systems and clinical samples, being used previously to predict regenerative responses in the damaged adult nervous system.     

Current progress in use of adipose derived stem cells in peripheral nerve regeneration

Unlike central nervous system neurons; those in the peripheral nervous system have the potential for full regeneration after injury. Following injury, recovery is controlled by schwann cells which replicate and modulate the subsequent immune response. The level of nerve recovery is strongly linked to the severity of the initial injury despite the significant advancements in imaging and surgical techniques. Multiple experimental model shave been used with varying successes to augment the natural regenerative processes which occur following nerve injury. Stem cell therapy in peripheral nerve injury may be an important future intervention to improve the best attainable clinical results. In particular adipose derived stem cells(ADSCs) are multipotent mesenchymal stem cells similar to bone marrow derived stem cells, which are thought to have neurotrophic properties and the ability to differentiate into multiple lineages. They are ubiquitous within adipose tissue; they can form many structures resembling the mature adult peripheral nervous system. Following early in vitro work; multiple small and large animal in vivo models have been used in conjunction with conduits, autografts and allografts to successfully bridge the peripheral nerve gap. Some of the ADSC related neuroprotective and regenerative properties have been elucidated however much work remains before a model can be used successfully in human peripheral nerve injury(PNI). This review aims to provide a detailed overview of progress made in the use of ADSC in PNI, with discussion on the role of a tissue engineered approach for PNI repair.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Progress of mesenchymal stem cell therapy for neural and retinal diseases

Complex circuitry and limited regenerative power make central nervous system(CNS)disorders the most challenging and difficult for functional repair.With elusive disease mechanisms,traditional surgical and medical interventions merely slow down the progression of the neurodegenerative diseases.However,the number of neurons still diminishes in many patients.Recently,stem cell therapy has been proposed as a viable option.Mesenchymal stem cells(MSCs),a widely-studied human adult stem cell population,have been discovered for more than 20 years.MSCs have been found all over the body and can be conveniently obtained from different accessible tissues:bone marrow,blood,and adipose and dental tissue.MSCs have high proliferative and differentiation abilities,providing an inexhaustible source of neurons and glia for cell replacement therapy.Moreover,MSCs also show neuroprotective effects without any genetic modification or reprogramming.In addition,the extraordinary immunomodulatory properties of MSCs enable autologous and heterologous transplantation.These qualities heighten the clinical applicability of MSCs when dealing with the pathologies of CNS disorders.Here,we summarize the latest progress of MSC experimental research as well as human clinical trials for neural and retinal diseases.This review article will focus on multiple sclerosis,spinal cord injury,autism,glaucoma,retinitis pigmentosa and age-related macular degeneration.     

Adult stem cells and bioengineering strategies for the treatment of cerebral ischemic stroke

The adult central nervous system (CNS) contains a population of neural stem cells, yet unlike many other tissues, has a very limited capacity for self-repair. Promoting tissue repair and functional recovery following CNS injury or disease is a high priority as there are currently no effective treatments towards this end for the treatment of disorders such as stroke, traumatic brain injury and spinal cord injury. Recent advances in stem cell biology have offered a number of enticing potential avenues and we will discuss these possibilities along with the associated challenges as they pertain to stroke. We will consider exogenous therapies involving the transplantation of adult stem cells, and the mobilization of endogenous stem cells, as well as drug delivery and tissue engineering strategies that enhance and complement the cell based strategies.     

Neural regeneration by regionally induced stem cells within poststroke brains: Novel therapy perspectives for stroke patients

Ischemic stroke is a critical disease which causes serious neurological functional loss such as paresis. Hope for novel therapies is based on the increasing evidence of the presence of stem cell populations in the central nervous system(CNS) and the development of stem-cell-based therapies for stroke patients. Although mesenchymal stem cells(MSCs) represented initially a promising cell source,only a few transplanted MSCs were present near the injured areas of the CNS.Thus, regional stem cells that are present and/or induced in the CNS may be ideal when considering a treatment following ischemic stroke. In this context, we have recently showed that injury/ischemia-induced neural stem/progenitor cells(i NSPCs) and injury/ischemia-induced multipotent stem cells(i SCs) are present within post-stroke human brains and post-stroke mouse brains. This indicates that i NSPCs/i SCs could be developed for clinical applications treating patients with stroke. The present study introduces the traits of mouse and human i NSPCs,with a focus on the future perspective for CNS regenerative therapies using novel i NSPCs/i SCs.     

神经干细胞的研究现状及运用前景

近年来的研究表明胚胎期和成年期动物的神经组织及人脑中可以分离出神经干细胞.神经干细胞能不断增殖并且具有分化成神经元、星型胶质细胞和少突胶质细胞的能力.神经干细胞的这种特性为中枢神经系统退行性病变和损伤的治疗打下了基础.对神经干细胞的分布、生物学特性、鉴定、增殖与分化及其治疗中枢神经系统疾病中的应用前景进行了综述.     

Biology and clinical application of neural stem cells

Neural stem cells, which exist in various regions of the CNS throughout the mammalian lifespan, can be expanded and induced to differentiate into neurons and glia in vitro and in vivo. Because of these characteristics, there has been increasing interest in the identification and characterization of neural stem cells and neural progenitor cells both for basic developmental biology studies and for therapeutic applications to the damaged brain. Transplantation of neural stem cells or their derivatives into a host brain and the proliferation and differentiation of endogenous stem cells by pharmacological manipulations are potential treatments for many neurodegenerative diseases and brain injuries, such as Parkinson's disease, brain ischemia and spinal cord injury. Continued progress in neural stem cell research is providing a new future for brain repair.     

Effects of the CNTF-collagen gel-controlled delivery system on rat neural stem/progenitor cells behavior

The injury of central nervous system (CNS) usually causes the cavity formation. Although transplantation of neural stem/precursor cells (NSPCs) into the lesioned area of CNS has been shown to be implicated in the functional restoration, the therapeutic result is limited by the poor survival of NSPCs as well as their insufficient proliferation and differentiation abilities. Type-1 collagen is considered as a candidate scaffold or drug delivery system to overcome the aforementioned obstacle. This study observ...     

Regeneration-based therapies for spinal cord injuries

Although it has been long believed that the damaged central nervous system does not regenerate upon injury, there is an emerging hope for regeneration-based therapy of the damaged central nervous system (CNS) due to the progress of developmental biology and regenerative medicine including stem cell biology. In this review, we have summarized recent studies aimed at the development of regeneration-based therapeutic approaches for spinal cord injuries, including therapy with anti-inflammatory cytokines, transplantation of neural stem/precursor cells and induction of axonal regeneration.