Stem cell‐based cell therapy for Huntington disease: A review

Huntington disease (HD) is a devastating neurodegenerative disorder and no proven medical therapy is currently available to mitigate its clinical manifestations. Although fetal neural transplantation has been tried in both preclinical and clinical investigations, the efficacy is not satisfactory. With the recent explosive progress of stem cell biology, application of stem cell‐based therapy in HD is an exciting prospect. Three kinds of stem cells, embryonic stem cells, bone marrow mesenchymal stem cells and neural stem cells, have previously been utilized in cell therapy in animal models of neurological disorders. However, neural stem cells were preferably used by investigators in experimental HD studies, since they have a clear capacity to become neurons or glial cells after intracerebral or intravenous transplantation, and they induce functional recovery. In this review, we summarize the current state of cell therapy utilizing stem cells in experimental HD animal models, and discuss the future considerations for developing new therapeutic strategies using neural stem cells.     

神经干细胞来源的研究与进展

神经干细胞是近期神经生物科学领域和神经外科领域的研究热点。应用神经干细胞自我更新和多分化潜能的生物学特性，移植治疗神经系统损伤或神经系统退行性疾病，已形成一种全新概念的神经外科治疗途径。然而如何获取大量的神经干细胞用于动物实验和临床应用成为限制该技术发展的难题，文章从介绍胚胎干细胞、成体神经干细胞和间充质干细胞的获取方法入手，希望将细胞移植治疗以一种安全有效的方式引入到临床治疗方案中。     

神经干细胞移植治疗小儿脑性瘫痪及所存在的问题

脑性瘫痪是儿童时期最常见且终生存在的运动性残疾,目前尚无有效治疗手段,细胞移植和基因治疗技术的飞速发展为治疗此类疾病带来了希望。近两年国内外出现有关神经干细胞移植治疗脑性瘫痪的报道,这给脑性瘫痪的治疗研究提供了新的思路。文章阐述了小儿脑性瘫痪的神经干细胞机制,并回顾近年来国内外关于神经干细胞移植在动物实验及临床中的有效应用,为神经干细胞治疗小儿脑性瘫痪的可行性提供依据。但神经干细胞移植治疗脑性瘫痪还存在一些问题：移植仍然存在免疫排斥反应;如何促进神经干细胞的快速增殖;如何实现神经干细胞的定向诱导分化;如何评价神经干细胞移植以后患儿的改善情况,移植时机,移植量,移植部位,移植方式等一系列问题均有待于基础和临床学科的共同研究和探讨。     

How to approach Alzheimer's disease therapy using stem cell technologies

The use of stem cells for neuroreplacement therapy is no longer science fiction - it is science fact. We have succeeded in producing neural cells in the brain using both neural and mesenchymal stem cell transplantation and even systemic injection using a small molecular compound. We have seen the improvement of cognitive function in animal models following the application of these stem cell technologies. These results may promise a bright future for stem cell based neuroreplacement therapies for neurodegenerative diseases including Alzheimer's disease (AD). However, we have to consider the pathophysiological environments of individual diseases before clinical applications can be introduced. We must find the factors in the pathology that may affect stem cell biology and overcome the negative effects on neuroreplacement. Here, we discuss not only the potential for therapeutic applications of stem cell strategies in neuropathological conditions, but also how to overcome the adverse effects on the biology of stem cells due to the factors that are altered under AD pathology.     

In vivo magnetic resonance tracking of magnetically labeled cells after transplantation.

During the last few years, the therapeutic use of stem and progenitor cells as a substitute for malfunctioning endogenous cell populations has received considerable attention. Unlike their current use in animal models, the introduction of therapeutic cells in patients will require techniques that can monitor their tissue biodistribution noninvasively. Among the different imaging modalities, magnetic resonance (MR) imaging offers both near-cellular (i.e., 25- to 50-mu) resolution and whole-body imaging capability. In order to be visualized, cells must be labeled with an intracellular tracer molecule that can be detected by MR imaging. Methods have now been developed that make it possible to incorporate sufficient amounts of superparamagnetic iron oxide into cells, enabling their detection in vivo using MR imaging. This is illustrated for (neural stem cell-derived) magnetically labeled oligodendroglial progenitors, transplanted in the central nervous system of dysmyelinated rats. Cells can be followed in vivo for at least 6 weeks after transplantation, with a good histopathologic correlation including the formation of myelin. Now that MR tracking of magnetically labeled cells appears feasible, it is anticipated that this technique may ultimately become an important tool for monitoring the efficacy of clinical (stem) cell transplantation protocols.     

Stem cell research in stroke: how far from the clinic?

Stem cell-based approaches hold much promise as potential novel treatments to restore function after stroke. Studies in animal models have shown that stem cell transplantation can improve function by replacing neurons or by trophic actions, modulation of inflammation, promotion of angiogenesis, remyelination and axonal plasticity, and neuroprotection. Endogenous neural stem cells are also potential therapeutic targets because they produce new neurons after stroke. Clinical trials are ongoing but there is currently no proven stem cell-based therapy for stroke. Preclinical studies and clinical research will be needed to optimize the therapeutic benefit and minimize the risks of stem cells in stroke.     

Recent advances in cell therapy for stroke

The last 50 years have witnessed the translation of stem cell therapy from the laboratory to the clinic for treating brain disorders, in particular stroke. From the focal stereotaxic transplantation to the minimally invasive intravenous and intraarterial delivery, stem cells display the ability to replenish injured cells and to secrete therapeutic molecules, altogether promoting brain repair. The increased stroke incidence in COVID-19 survivors poses as a new disease indication for cell therapy, owing in part to the cells’ robust anti-inflammatory properties. Optimization of the cell transplant regimen will ensure the safe and effective clinical application of cell therapy in stroke and relevant neurological disorders.     

Cell-replacement therapy with stem cells in neurodegenerative diseases

In the past few years, research on stem cells has expanded greatly as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results, in addition to replacement of lost cells. The biological issue needs to be clarified in order to maximize the potential for effective therapies. The absence of any effective pharmacological treatment and preliminary data both in experimental and clinical settings has recently identified Amyotrophic Lateral Sclerosis (ALS) as an ideal candidate disease for the development of stem cell therapy in humans. Preliminary stem transplantation trials have already been performed in patients. The review discusses relevant topics regarding the application of stem cell research to ALS but in general to other neurodegenerative diseases debating in particular the issue of transdifferentiation, endogenous neural stem cell, and factors influencing the stem cell fate.     

脐血干细胞移植治疗心肌梗死的作用与机制

背景：多项基础和临床研究表明，干细胞移植可以改善心肌梗死后心力衰竭患者的心脏功能。 目的：总结脐血干细胞移植治疗心肌梗死的的作用与机制。 方法：由第一作者检索2000/2009 PubMed数据库及CNKI、万方数据库有关脐血干细胞移植治疗心肌梗死基础研究方面的文献。 结果与结论：干细胞移植在治疗急性心肌梗死方面已表现出传统治疗方法无法比拟的优势，而目前一系列基础研究证实人脐血干细胞有望成为更为理想的细胞源，但因其尚处于探索性研究阶段，仍有许多问题有待解决，诸如人脐血干细胞的体外分离、培养，最适宜的移植治疗时间，最有利的移植途径，最佳的移植数量，移植细胞的存活率如何，移植后能否分化为心肌细胞，分化程度如何以及其疗效和安全性等。     

神经干细胞移植途径的理论研究进展

神经干细胞是指来源于神经组织或能分化为神经组织、具有自我更新能力和多向分化潜能的一类细胞,近年来神经干细胞研究成为治疗神经退行性疾病和中枢神经系统损伤的热点。移植入宿主体内的神经干细胞能够向神经系统病变部位趋行、聚集,并能够存活、增殖、分化为神经元和/或胶质细胞,从而促进宿主缺失功能的部分恢复。如何将神经干细胞准确、安全移植到宿主体内,并最终迁移、聚集到脑内功能缺失部位成为该技术发展的一个重要环节。文章就目前神经干细胞动物实验和临床研究中较多采取的移植途径,包括局部注射移植、经脑脊液注射移植、经血液循环注射移植的研究进展加以概述,比较这3种方法各自的优缺点,分析神经干细胞移植的安全性和有效性,探讨哪种移植途径才是神经干细胞最适合的移植方法。     

Cell-based transplantation strategies to promote plasticity following spinal cord injury

Cell transplantation therapy holds potential for repair and functional plasticity following spinal cord injury (SCI). Stem and progenitor cells are capable of modifying the lesion environment, providing structural support and myelination and increasing neurotrophic factors for neuroprotection and endogenous activation. Through these effects, transplanted cells induce plasticity in the injured spinal cord by promoting axonal elongation and collateral sprouting, remyelination, synapse formation and reduced retrograde axonal degeneration. In light of these beneficial effects, cell transplantation could be combined with other treatment modalities, such as rehabilitation and immune modulation, to provide a synergistic functional benefit. This review will delineate 1) stem/progenitor cell types proposed for cell transplantation in SCI, 2) in vitro evidence of cell-induced mechanisms of plasticity, 3) promotion of functional recovery in animal models of SCI, 4) successful combinatorial strategies using cell transplantation. Current treatment modalities for SCI provide modest efficacy, especially in chronic stages of SCI. Hence, combinatorial stem cell transplantation strategies which could potentially directly address tissue sparing and neuroplasticity in chronic SCI show promise. Rigorous evaluation of combinatorial approaches using stem cell transplantation with appropriate preclinical animal models of SCI is needed to advance therapeutic strategies to the point where clinical trials are appropriate. Given the high patient demand for and clinical trial precedent of cell transplantation therapy, combination stem cell therapies have the promise to provide improved quality of life for individuals, with corresponding socioeconomic benefit.     

Hematopoietic stem cell transplantation for multiple sclerosis: current status and future challenges

PURPOSE OF REVIEW: This article reviews recent advances in clinical trials of hematopoietic stem cell transplantation as a therapy for multiple sclerosis, and progress in exploring the potential for neural repair of hematopoietic-derived precursors. RECENT FINDINGS: Important recent findings are that hematopoietic stem cell transplantation can completely suppress the inflammatory component of multiple sclerosis, hematopoietic stem cells can migrate into the central nervous systems of rodents and humans, and can differentiate into cells expressing neural and glial markers. Hematopoietic stem cells also have neural and myelin repair potential. The heterogeneity of transplant regimens, the selection of patients at different stages of disease in clinical trials, and the limited duration of follow-up all currently preclude the evaluation of the long-term clinical benefits of hematopoietic stem cell transplantation for multiple sclerosis. SUMMARY: Hematopoietic stem cell transplantation is an experimental treatment that shows strong effects on the inflammatory component of multiple sclerosis. On the basis of experience acquired from initial pilot studies, controlled clinical trials are now being designed to verify long-term clinical efficacy. Selecting patients at high risk in the earlier stages of the disease that is dominated by inflammation, and monitoring objectively disease activity by magnetic resonance imaging will be critically important in these studies. Recent advances on the migratory potential and on the differentiation plasticity of hematopoietic stem cells have opened new opportunities for remyelination and axonal repair strategies for multiple sclerosis.     

Stem cell transplantation into the central nervous system and the control of differentiation

Recent advances in stem cell biology, including methods of cell amplification and control of differentiation in vitro, provide us with new and powerful tools with which to explore the cellular, molecular, and genetic factors affecting cell survival, proliferation, differentiation, and differentiation potential. Mitigating this vein of enthusiasm are the results of stem cell transplantation studies, which highlight our inability to control the fate of stem cell populations following transplantation to the central nervous system (CNS). Differentiation of transplanted cells is strongly influenced by the environmental signals and cellular deficiencies operating at the site of implantation, over which we can exert little or no control. Where stem cell transplantation-mediated repair of the injured CNS has been demonstrated most successfully, the transplant environments have invariably been simplistic, and transplantation into the complex and reactive environment of a CNS injury site generally results in migration from the site of implantation followed by glial cell differentiation. Together, these findings suggest that the most significant advances for the stem cell transplantation field will come from research strategies that include predifferentiation of stem cells prior to transplant and studies that further our understanding of the factors affecting stem cell differentiation in the complex environment of the CNS in vivo.     

异基因造血干细胞移植中急性移植物抗宿主病的研究状况

目前认为,异基因造血干细胞移植可通过免疫细胞介导的移植物抗白血病效应消除体内残留的肿瘤细胞,达到治愈的目的。但移植物抗宿主病,尤其急性移植物抗宿主病,是异基因造血干细胞移植应用中最棘手的问题,是移植后致残及相关死亡的主要原因。而控制移植物抗宿主病的药物大多抑制移植物抗白血病效应,同时付出了移植效能降低、感染机会增加的代价。因此,理想的方法是寻找使T细胞处于激活状态,保持移植物抗白血病效应,但同时又抑制特异性同种抗原。一些对经典抗原提呈细胞、树突状细胞等的新发现,移植方式的改良以及间充质干细胞和调节性T细胞的应用等,为移植物抗宿主病的防治提示了新的方向。     

Stem cell therapy for cerebral ischemia: from basic science to clinical applications

Recent stem cell technology provides a strong therapeutic potential not only for acute ischemic stroke but also for chronic progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis with neuroregenerative neural cell replenishment and replacement. In addition to resident neural stem cell activation in the brain by neurotrophic factors, bone marrow stem cells (BMSCs) can be mobilized by granulocyte-colony stimulating factor for homing into the brain for both neurorepair and neuroregeneration in acute stroke and neurodegenerative diseases in both basic science and clinical settings. Exogenous stem cell transplantation is also emerging into a clinical scene from bench side experiments. Early clinical trials of intravenous transplantation of autologous BMSCs are showing safe and effective results in stroke patients. Further basic sciences of stem cell therapy on a neurovascular unit and neuroregeneration, and further clinical advancements on scaffold technology for supporting stem cells and stem cell tracking technology such as magnetic resonance imaging, single photon emission tomography or optical imaging with near-infrared could allow stem cell therapy to be applied in daily clinical applications in the near future.     

Cell replacement therapy for Parkinson's disease: how close are we to the clinic?

Cell replacement therapy (CRT) offers great promise as the future of regenerative medicine in Parkinson′s disease (PD). Three decades of experiments have accumulated a wealth of knowledge regarding the replacement of dying neurons by new and healthy dopaminergic neurons transplanted into the brains of animal models and affected patients. The first clinical trials provided the proof of principle for CRT in PD. In these experiments, intrastriatal transplantation of human embryonic mesencephalic tissue reinnervated the striatum, restored dopamine levels and showed motor improvements. Sequential controlled studies highlighted several problems that should be addressed prior to the wide application of CRT for PD patients. Moreover, owing to ethical and practical problems, embryonic stem cells require replacement by better-suited stem cells. Several obstacles remain to be surpassed, including identifying the best source of stem cells for A9 dopaminergic neuron generation, eliminating the risk of tumor formation and the development of graft-induced dyskinesias, and standardizing dopaminergic cell production in order to enable clinical application. In this article, we present an update on CRT for PD, reviewing the research milestones, various stem cells used and tailored differentiation methods, and analyze the information gained from the clinical trials.     

自体干细胞移植治疗肝硬化腹水概况

目前治疗肝硬化主要有3类细胞移植方法：肝细胞移植、肝干细胞移植和骨髓干细胞移植。前两种方法存在来源缺乏、移植细胞体内存活和增殖困难等问题。骨髓干细胞移植则来源方便,不受供体缺乏的限制,还可免除免疫排斥反应的发生。中毒性、炎症性、以及慢性损伤性肝脏疾病,早、中期肝硬化,难治性低蛋白血症、难治性腹水、反复发作黄疸等患者都适合直接接受骨髓肝干细胞移植。国内外研究及临床应用均表明,自体干细胞移植治疗肝硬化腹水等肝病效果出色,具有广泛推广价值,综合起来,主要有3大优点：效果明显、费用低廉、技术风险小。     

Transplantation of myelinating cells as regenerative therapy for multiple sclerosis - experimental basis and present state of clinical studies

Currently available therapies for multiple sclerosis (MS) delay disease progression via immunomodulation or immunosuppression. A persisting neurological deficit is mostly irreversible. Thus, a reparative treatment is urgently warranted. After positive results in animal models, clinical trials to promote endogenous remyelination with intravenous immunoglobulins (IVIg) or the growth factor IGF-1 were performed, unfortunately without clinical improvement. Another possibility to achieve remyelination is the transplantation of myelinating cells into the central nervous system. Proof of principle and demonstration of the functionality were shown in numerous experiments, and a first clinical trial in patients with MS has started. Although there are still several open questions, many are specific to MS and can not be answered in an animal model. This first trial will show if cell transplantation is a feasible concept in MS and whether the transplanted cells will survive and form new myelin. Schwann cells are currently the most promising cells to be transplanted, due to the advantages of an autologous transplantation from the patient's sural nerve biopsy, possibility to expand the cells in culture, and the possibility that they may escape the ongoing inflammatory reaction in MS. Other cell types are available, including stem cells, which are in the centre of a lively discussion. The results of the ongoing trial must be awaited before other transplant studies are performed to tackle other yet unresolved problems. At the time, it seems unlikely that cell transplantation will become clinical practice in the near future.     

The role of noninvasive cellular imaging in developing cell-based therapies for neurodegenerative disorders

Stem and progenitor cells from various sources are currently recognized as entities with potential for the treatment of numerous neurodegenerative diseases. It has been observed in many animal models that transplantation of stem cells induces functional improvement. As a result of these findings, the first clinical cell transplantation trials were initiated, including those for Parkinson's disease and cerebral ischemia patients. However, in many patients, although modest improvements have been observed, these improvements were not sufficient to warrant invasive and possibly risky cell therapy. Thus, it is apparent that therapeutic success requires a better understanding of the mechanisms of action and the ability to control these mechanisms that underlie functional improvements, permitting amplification of the therapeutic effect. Considering the complexity of the nervous system, the task of repairing damaged or dysfunctional brain tissue with na?ve cellular elements that require spatially and temporally accurate governance may seem daunting. However, the hope for faster and more inclusive progress in this field arises from recent developments in medical biotechnology that offers scientists increasingly sophisticated tools to study and control biological processes. One such technology with great potential for neurotransplantation is noninvasive cellular imaging. This tool allows real-time 'supervision' of grafted cells, as well as monitoring biodistribution and development. In this review, we highlight the current challenges in the field of cell-based therapy for neurodegenerative disorders and outline the role and capabilities of different cellular imaging techniques in addressing those issues.     

Advances in stroke neuroprotection: hyperoxia and beyond

Refinements in patient selection, improved methods of drug delivery, use of more clinically relevant animal stroke models, and the use of combination therapies that target the entire neurovascular unit make stroke neuroprotection an achievable goal. This article provides an overview of the major mechanisms of neuronal injury and the status of neuroprotective drug trials and reviews emerging strategies for treatment of acute ischemic stroke. Advances in the fields of stem cell transplantation, stroke recovery, molecular neuroimaging, genomics, and proteomics will provide new therapeutic avenues in the near future. These and other developments over the past decade raise expectations that successful stroke neuroprotection is imminent.