Stem cell treatment for Crohn’s disease

While stem cell-based treatments have been established as a clinical standard of care for some conditions, such as hematopoietic stem cell transplants for cancer, the scope of potential stem cell-based therapies has expanded in recent years due to advances in stem cell research, paving the way for the increasing utilization of stem cell therapies in severe immune-mediated diseases including inflammatory bowel diseases (IBDs) and, in particular, Crohn’s disease. Both hematopoietic stem cells and mesenchymal (stromal) stem cells are considered to be of potential therapeutic benefit in immune-mediated conditions. A growing body of experimental and clinical evidence shows that hematopoietic stem cell transplant induces long-lasting remission in a majority of patients with active severe Crohn’s disease refractory to drug treatments, and the differential effect of potent immunosuppression and immune reconstitution in this setting is under evaluation. Mesenchymal stem cells have been shown to exert immunomodulatory action on various types of immune-mediated diseases, and in experimental models of IBD, but evaluation of the potential efficacy of this therapy in IBD is still in the early stages.     

Is There a Future for Neural Transplantation?

Traditionally neural transplantation has had as its central tenet the replacement of missing neurons that have been lost because of neurodegenerative processes, as exemplified by diseases such as Parkinson disease (PD). However, the effectiveness and widespread application of this approach clinically has been limited, primarily because of the poor donor supply of human fetal neural tissue and the incomplete neurobiological understanding of the circuit reconstruction required to normalize function in these diseases. So, in PD the progress from promising neural transplantation in animal models to proof-of-principle, open-labeled clinical transplants, to randomized, placebo-controlled studies of neural transplantation has not been straightforward. The emergence of previously undescribed adverse effects and lack of significant functional advantage in recent clinical studies has been disappointing and has served to cast a new, and perhaps more realistic, perspective on this treatment approach. In fact, there have been calls by some involved in neural transplantation to return to the drawing board before pressing on with further clinical trials, and the return to basic experimentation. This therefore precipitates the question — is there a future for neural transplantation? It is important to remember that there are a number of possible explanations for the disappointing results from the recent clinical trials in PD, ranging from the mode of transplantation to patient selection. Nevertheless, almost irrespective of these reasons for the current trial results, there have always been significant practical and ethical problems with using human fetal tissue, and so a number of alternative cell sources have been investigated. These alternative sources include stem cells, which are attractive for cell-based therapies because of their potential ease of isolation, propagation and manipulation, and their ability in some cases to migrate to areas of pathology and differentiate into specific and appropriate cell types. Furthermore, the availability of stem cells derived from non-embryonic sources (e.g. adult stem cells derived from the sub-ventricular zone) has removed some of the ethical limitations associated with the use of embryonic human tissue. These potentially beneficial aspects of stem cells means that there is a future for neural transplantation as a means of treating patients with a range of neurological disorders, although whether this will ever translate into a truly effective, widely available therapy remains unknown.     

Autophagic death of adult hippocampal neural stem cells following insulin withdrawal

Novel therapeutic approaches using stem cell transplantation to treat neurodegenerative diseases have yielded promising results. However, survival of stem cells after transplantation has been very poor in animal models, and considerable efforts have been directed at increasing the viability of engrafted stem cells. Therefore, understanding the mechanisms that regulate survival and death of neural stem cells is critical to the development of stem cell-based therapies. Hippocampal neural (HCN) stem cells derived from the adult rat brain undergo cell death following insulin withdrawal, which is associated with downregulation of antiapoptotic Bcl-2 family members. To understand the type of cell death in HCN cells following insulin withdrawal, apoptosis markers were assessed. Of note, DNA fragmentation or caspase-3 activation was not observed, but rather dying cells displayed features of autophagy, including increased expression of Beclin 1 and the type II form of light chain 3. Electron micrographs showed the dramatically increased formation of autophagic vacuoles with cytoplasmic contents. Staurosporine induced robust activation of caspase-3 and nucleosomal DNA fragmentation, suggesting that the machinery of apoptosis is intact in HCN cells despite the apparent absence of apoptosis following insulin withdrawal. Autophagic cell death was suppressed by knockdown of autophagy-related gene 7, whereas promotion of autophagy by rapamycin increased cell death. Taken together, these data demonstrate that HCN cells undergo a caspase-independent, autophagic cell death following insulin withdrawal. Understanding the mechanisms governing autophagy of adult neural stem cells may provide novel strategies to improve the survival rate of transplanted stem cells for treatment of neurodegenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.     

Stem Cell Therapy for Bronchopulmonary Dysplasia: Bench to Bedside Translation

Bronchopulmonary dysplasia (BPD), a chronic lung disease affecting very premature infants, is a major cause of mortality and long-term morbidities despite of current progress in neonatal intensive care medicine. Though there has not been any effective treatment or preventive strategy for BPD, recent stem cell research seems to support the assumption that stem cell therapy could be a promising and novel therapeutic modality for attenuating BPD severity. This review summarizes the recent advances in stem cell research for treating BPD. In particular, we focused on the preclinical data about stem cell transplantation to improve the lung injury using animal models of neonatal BPD. These translational research provided the data related with the safety issue, optimal type of stem cells, optimal timing, route, and dose of cell transplantation, and potency marker of cells as a therapeutic agent. Those are essential subjects for the approval and clinical translation. In addition, the successful phase I clinical trial results of stem cell therapies for BPD are also discussed.     

Neural stem cell systems: diversities and properties after transplantation in animal models of diseases

Currently available effective treatments of the diseased or damaged central nervous system (CNS) are restricted to a limited pharmacological relief of symptoms or those given to avoid further damage. Therefore the search is on for treatments that can restore function in the CNS. During recent years replacement of damaged neurons by cell transplantation is being enthusiastically explored as a potential treatment for many neurodegenerative diseases, stroke and traumatic brain injury. Several references in both scientific journals and popular newspapers concerning different types of cultured stem cells, potentially exploitable to treat pathological conditions of the brain, raise important questions pertinent to the fundamental and realistic differences between grafts of primary neural cells and the transplantation of in vitro expanded neural stem cells (NSCs). Our aim is to review the available information on the grafting of different NSC types into the adult rodent brain, focusing on critical aspects for the development of clinical therapies to replace damaged neurons.     

Neuronal generation from somatic stem cells: current knowledge and perspectives on the treatment of acquired and degenerative central nervous system disorders

Stem cell transplantation through cell replacement or as vector for gene delivery is a potential strategy for the treatment of neurodegenerative diseases. Several studies have reported the transdifferentiation of different somatic stem cells into neurons in vitro or after transplantation into animal models. This observation has pointed out the perspective of using an ethical and accessible cell source to "replace" damaged neurons or provide support to brain tissue. However, recent findings such as the cell fusion phenomenon have raised some doubts about the real existence of somatic stem cell plasticity. In this review, we will discuss current evidence and controversial issues about the neuroneogenesis from various sources of somatic cells focusing on the techniques of isolation, expansion in vitro as well as the inductive factors that lead to transdifferentiation in order to identify the factors peculiar to this process. The morphological, immunochemical, and physiological criteria to correctly judge whether the neuronal transdifferentation occurred are critically presented. We will also discuss the transplantation experiments that were done in view of a possible clinical therapeutic application. Animal models of stroke, spinal cord and brain trauma have improved with Mesenchymal Stem Cells or Bone Marrow transplantation. This improvement does not seem to depend on the replacement of the lost neurons but may be due to increased expression levels of neurotrophic factors, thus suggesting a beneficial effect of somatic cells regardless of transdifferentiation. Critical understanding of available data on the mechanisms governing the cell fate reprogramming is a necessary achievement toward an effective cell therapy.     

Advances in Mesenchymal Stem Cell-based Strategies for Cartilage Repair and Regeneration

Significant research efforts have been undertaken in the last decade in the development of stem cell-based therapies for cartilage repair. Among the various stem cell sources, mesenchymal stem cells (MSCs) demonstrate great promise and clinical efficacy in cartilage regeneration. With a deeper understanding of stem cell biology, new therapeutics and new bioengineering approaches have emerged and showed potential for further developments. Of note, there has been a paradigm shift in applying MSCs for tissue regeneration from the use of stem cells for transplantation to the use of stem cell-derived matrix and secretome components as therapeutic tools and agents for cartilage regeneration. In this review, we will discuss the emerging role of MSCs in cartilage regeneration and the most recent advances in development of stem cell-based therapeutics for cartilage regeneration.     

神经系统疾病的干细胞治疗☆

背景：干细胞具有自我更新和多向分化的生物学特性,在生理或病理情况下能维持组织器官内环境的稳定,近年被广泛用于再生医学的研究。 目的：对神经系统疾病的干细胞治疗进展进行综述。 方法：通过Pubmed数据库检索有关干细胞治疗神经系统疾病的相关文献。检索词为“stem cells、Nervous system diseases、therapy”。初检得到298篇文献,最终保留54篇符合标准的文献进行分析。 结果与结论：经过近些年的研究,干细胞被认为是神经损伤和变性疾病的一个很有前景的治疗手段。通过干细胞的移植,取代受损的神经细胞,促进受损神经网络的恢复从而重建神经功能。     

Retinal stem cells: mechanism of differentiation and therapeutic application

Retinal dystrophies are rarely curable diseases and several avenues of research are being pursued, such replacement therapies and pharmacological treatment. Among them, the transplantation of functional retinal cells has been envisaged in order to restore vision in patients who have these diseases by repopulating the damaged retina and/or by rescuing retinal neurons from further degeneration. Over the past few years, identification and characterization of stem cells has opened new avenues in cell-replacement therapy. Since retinal stem cells are already present during embryonic development, they persist in the adult mammalian eye only in the ciliary marginal zone, even a stem cell potential has been described for the Müller glia in the retina. This result opened possibilities of regeneration by mobilizing endogenous stem cells to respond to injury. Regarding the transplantation studies, in all experiments using different types of stem cells (retinal progenitors, neural stem cells, bone marrow-derived stem cells and ES cells), despite their incorporation within the host's retina, the transplanted cells failed to express retina-specific markers and to establish synaptic connections. Therefore, the true potential of the different stem cells in retina repair can only be realized with more information about mechanisms that regulate their proliferation and differentiation; and by development of techniques that allow their prospective identification and enrichment.     

Myogenic stem cells: regeneration and cell therapy in human skeletal muscle

Human skeletal muscle has been considered as an ideal target for cell-mediated therapy. However, the positive results obtained in dystrophic animal models using the resident precursor satellite cell population have been followed by discouraging evidences obtained in the clinical trials involving Duchenne muscular dystrophy patients. This text reviews the recent advances that many groups have achieved to identify from the stem cell compartment putative candidates for cell therapy. We focused our attention on stem cells with myogenic potential which might be able to improve transplantation efficiency and therefore could be used as a therapeutic tool for neuromuscular diseases.     

Human embryonic stem cell lines are contaminated: what should we do?

Human embryonic stem (hES) cells have the potential to differentiate into any desired cells and to be used in cell replacement therapies for some diseases. However, existing hES cell lines would not be suitable for the therapies as they are contaminated with other biological products. In order to produce the safest hES cell lines for therapeutic purposes, all steps for the establishment of hES cell lines must avoid the use of animal serum and/or animal feeder cell lines. Safe and fast approaches to producing hES cell lines based on recent research advances in both humans and animals have been suggested.     

Stem cell gene therapy for chronic renal failure

Recently, stem cell research has attracted considerable attention because it could be used for the regeneration of damaged organs that are untreatable by conventional techniques, and several stem cells (or progenitor cells), such as endothelial stem cells and neural stem cells have been discovered. Following the progression of this field of research, the potential for stem cell gene therapy has increased and several therapeutic benefits have already been reported. Although this approach was originally investigated for fatal or hereditary diseases, chronic renal failure is also a candidate for stem cell gene therapy. We have proposed two different therapeutic strategies for chronic renal failure depending on whether the bone marrow stem cells differentiate and commit into mesenchymal or hematopoietic stem cells. In the case of diseases, which need reconstitution of residential renal cells, such as congenital enzyme deficiency diseases, mesenchymal stem cells should be transplanted, and in contrast, hematopoietic stem cells may be used for gene delivery for diseases, which need foreign cytokines and growth factors, such as glomerulonephritis. This article reviews the recent investigation on this tailor-made stem cell gene therapy for chronic renal failure and discusses the potential of this novel strategy and the major practical challenges of its clinical application.     

Potential roles of bone marrow stem cells in stroke therapy

There is a need for improved therapies, in terms of utility and effectiveness, for stroke patients; however, over the years, numerous clinical trials of potential drugs have failed to demonstrate positive results. The emerging field of stem cell research has raised several hopes of a therapy for neurological diseases, including stroke. This review discusses the recent clinical trials and pilot studies using stem cells in stroke patients and highlights key issues that must be addressed to improve the chances of successfully developing a new strategy for stroke patients using adult stem cells.     

诱导多功能干细胞在视网膜疾病中的应用

背景：视网膜疾病以视网膜细胞损伤或凋亡为特点,缺乏理想的治疗方法。诱导多功能干细胞具有自我更新和多向分化潜能,不存在伦理道德问题,为干细胞移植治疗提供了新的来源,是当前研究的热点。 目的：综述诱导多功能干细胞在视网膜疾病治疗中应用的研究进展。 方法：第一作者应用计算机检索PubMed 相关文献,检索时间为2006年至2011年,检索词“induced pluripotent stem cells,retinal,photoreceptor,retinal pigment epithelium,retinal ganglion cell”并限定文献语言种类为English。共纳入42篇文章进行综述。 结果与结论：诱导多功能干细胞可以诱导分化为视网膜细胞,为细胞移植治疗提供来源,也可以作为疾病的模型来研究发病机制或者药物筛选,因此诱导多功能干细胞治疗视网膜疾病具有很大前景。然而,体细胞成功诱导为诱导多功能干细胞的效率低,并且存在致瘤的风险,有待更进一步研究。     

Stem cell technology for the study and treatment of motor neuron diseases

Amyotrophic lateral sclerosis and spinal muscular atrophy are devastating neurodegenerative diseases that lead to the specific loss of motor neurons. Recently, stem cell technologies have been developed for the investigation and treatment of both diseases. Here we discuss the different stem cells currently being studied for mechanistic discovery and therapeutic development, including embryonic, adult and induced pluripotent stem cells. We also present supporting evidence for the utilization of stem cell technology in the treatment of amyotrophic lateral sclerosis and spinal muscular atrophy, and describe key issues that must be considered for the transition of stem cell therapies for motor neuron diseases from bench to bedside. Finally, we discuss the first-in-human Phase I trial currently underway examining the safety and feasibility of intraspinal stem cell injections in amyotrophic lateral sclerosis patients as a foundation for translating stem cell therapies for various neurological diseases.     

Stem Cell Transplantation and Physical Exercise in Parkinson’s Disease,a Literature Review of Human and Animal Studies

The absence of effective and satisfactory treatments that contribute to repairing the dopaminergic damage caused by Parkinson’s Disease (PD) and the limited recovery capacity of the nervous system are troubling issues and the focus of many research and clinical domains. Recent advances in the treatment of PD through stem cell (SC) therapy have recognized their promising restorative and neuroprotective effects that are implicated in the potentiation of endogenous mechanisms of repair and contribute to functional locomotor improvement. Physical exercise (PE) has been considered an adjuvant intervention that by itself induces beneficial effects in patients and animal models with Parkinsonism. In this sense, the combination of both therapies could provide synergic or superior effects for motor recovery, in contrast with their individual use. This review aims to provide an update on recent progress and the potential effectiveness of SC transplantation and PE for the treatment of locomotor deficits in PD. It has reviewed the neuropathological pathways involved in the classical motor symptoms of this condition and the mechanisms of action described in experimental studies that are associated with locomotor enhancement through exercise, cellular transplantation, and their union in some neurodegenerative conditions.     

Present Status and Perspectives of Stem Cell-Based Therapies for Gastrointestinal Diseases

In recent years the interest in stem cell-based therapies for gastrointestinal injury has been increasing continuously. From the clinical point of view, transplantation of bone marrow derived stem cells may represent an alternative therapy for gastrointestinal injury, such as radioactive injury, inflammatory bowel disease, and other refractory gastrointestinal tract injury. There were several reports indicated that bone marrow derived stem cells located in the injured gastrointestinal tract and contributed to its regeneration by differentiating into functional epithelia cells or infusing with the gastrointestinal stem cells. Although the concept of cell-based therapy for various diseases of the gastrointestinal is widely accepted, the practical approach in humans remains difficult. Here we discussed the recent published data on clinical and experimental bone marrow stem cell transplantation and the possible role of stem cells in gastrointestinal tissue repair.     

Pluripotent Stem Cells and Other Innovative Strategies for the Treatment of Ocular Surface Diseases

The cornea provides two thirds of the refractive power of the eye and protection against insults such as infection and injury. The outermost tissue of the cornea is renewed by stem cells located in the limbus. Depletion or destruction of these stem cells may lead to blinding limbal stem cell deficiency (LSCD) that concerns millions of patients around the world. Innovative strategies based on adult stem cell therapies have been developed in the recent years but they are still facing numerous unresolved issues, and the long term results can be deceiving. Today there is a clear need to improve these therapies, and/or to develop new approaches for the treatment of LSCD. Here, we review the current cell-based therapies used for the treatment of ocular diseases, and discuss the potential of pluripotent stem cells (embryonic and induced pluripotent stem cells) in corneal repair. As the secretion of paracrine factors is known to have a crucial role in maintaining stem cell homeostasis and in wound repair, we also consider the therapeutic potential of a promising novel pathway, the exosomes. Exosomes are nano-sized vesicles that have the ability to transfer RNAs and proteins to recipient cells, and several studies demonstrated their role in cell protection and wound healing. Exosomes could circumvent the hurdles of stem-cell based approaches, and they could become a strong candidate as an alternative therapy for ocular surface diseases.     

Mitochondrial function and dynamics in neural stem cells and neurogenesis: Implications for neurodegenerative diseases

Mitochondria have been largely described as the powerhouse of the cell and recent findings demonstrate that this organelle is fundamental for neurogenesis. The mechanisms underlying neural stem cells (NSCs) maintenance and differentiation are highly regulated by both intrinsic and extrinsic factors. Mitochondrial-mediated switch from glycolysis to oxidative phosphorylation, accompanied by mitochondrial remodeling and dynamics are vital to NSCs fate. Deregulation of mitochondrial proteins, mitochondrial DNA, function, fission/fusion and metabolism underly several neurodegenerative diseases; data show that these impairments are already present in early developmental stages and NSC fate decisions. However, little is known about mitochondrial role in neurogenesis. In this Review, we describe the recent evidence covering mitochondrial role in neurogenesis, its impact in selected neurodegenerative diseases, for which aging is the major risk factor, and the recent advances in stem cell-based therapies that may alleviate neurodegenerative disorders-related neuronal deregulation through improvement of mitochondrial function and dynamics.     

不同干细胞来源外泌体在心血管疾病治疗中的应用、作用及问题

文题释义：外泌体：是一种直径为30-100 nm,由细胞内多泡体与细胞膜融合后释放到细胞外基质中的膜囊泡。外泌体存在于多种体液中,如血清、唾液、羊水、母乳和尿液,同时在细胞培养基中也有外泌体的释放。外泌体含有DNA片段、mRNA、小RNA、功能蛋白及转录因子等多种具有生物活性的物质,其膜结构还表达多种抗原、抗体分子,能产生各种生物学效应,从而在临床治疗疾病中具有广泛的应用前景。 干细胞来源外泌体在心血管疾病方面的应用价值：干细胞来源外泌体有效地规避了干细胞移植带来的缺陷,如免疫排斥反应、致瘤性和输注毒性,这些局限性使干细胞在心血管疾病治疗中黯然失色。干细胞来源外泌体可通过移植到受体心脏来调节各种细胞过程,如增殖、凋亡、应激反应以及分化和血管生成等。因此,干细胞来源外泌体可以作为替代干细胞治疗心血管疾病安全有效的手段。 背景：外泌体含有DNA片段、mRNA、小RNA、功能蛋白及转录因子等多种具有生物活性的物质,同时其膜结构还表达多种抗原、抗体分子,从而能产生各种生物学效应。近年来的研究结果表明其具有类似于干细胞移植的治疗作用,可用于代替干细胞移植治疗心血管疾病。 目的：总结不同干细胞来源外泌体在心血管疾病治疗中的应用,为外泌体治疗心血管疾病提供参考及依据。 方法：通过检索 PubMed数据库2005至 2019年期间的相关文章,检索词为“exosomes,cardiovascular disease,embryonic stem cells,induced pluripotent stem cells,mesenchymal stem cells”,同时检索中国知网、维普数据库2014 至 2019年期间的相关文章,检索词为“外泌体,心血管疾病,胚胎干细胞,诱导多能干细胞,间充质干细胞”。对文献资料及参考文献进行逐一查阅。 结果与结论：干细胞来源外泌体比干细胞移植更安全、有效,在心血管疾病的治疗方面具有巨大潜力,但关于外泌体功能及用途的研究仍处于起步阶段,此外外泌体含量低,提取过程繁琐等问题限制了其临床应用。 ORCID: 0000-0001-8179-1040(刘卒) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程