Stem cell therapies in age-related neurodegenerative diseases and stroke

Aging, a complex process associated with various structural, functional and metabolic changes in the brain, is an important risk factor for neurodegenerative diseases and stroke. These diseases share similar neuropathological changes, such as the formation of misfolded proteins, oxidative stress, loss of neurons and synapses, dysfunction of the neurovascular unit (NVU), reduction of self-repair capacity, and motor and/or cognitive deficiencies. In addition to gray matter dysfunction, the plasticity and repair capacity of white matter also decrease with aging and contribute to neurodegenerative diseases. Aging not only renders patients more susceptible to these disorders, but also attenuates their self-repair capabilities. In addition, low drug responsiveness and intolerable side effects are major challenges in the prevention and treatment of senile diseases. Thus, stem cell therapies—characterized by cellular plasticity and the ability to self-renew—may be a promising strategy for aging-related brain disorders. Here, we review the common pathophysiological changes, treatments, and the promises and limitations of stem cell therapies in age-related neurodegenerative diseases and stroke.     

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。     

Autophagy in neurodegenerative diseases: pathogenesis and therapy

The most prevalent pathological features of many neurodegenerative diseases are the aggregation of misfolded proteins and the loss of certain neuronal populations. Autophagy, as major intracellular machinery for degrading aggregated proteins and damaged organelles, has been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. In this review, we summarize most recent research progress in this topic and provide a new perspective regarding autophagy regulation on the pathogenesis of neurodegenerative diseases. Finally, we discuss the signaling molecules in autophagy‐related pathways as therapeutic targets for the treatment of these diseases.     

Stem cell therapy for digestive tract diseases: current state and future perspectives

Diseases of the digestive tract are complex and encompass a broad spectrum of different pathogeneses (inflammatory, ischemic, neoplastic, and functional deficit). The digestive tract is not a sterile environment, and its organs are composed of tissues with different embryologic origin and different morphologic and functional complexity. As a consequence, the management of these diseases is often challenging. Stem cell (SC) therapy has yielded some promising results in preclinical studies, and, recently, some approaches have been tested clinically. Indeed, during the last 5 years, the number of clinical trials with SCs for treatment of digestive tract diseases has increased 10-fold. The most advanced programs involve liver failure, Crohn's disease, and fistulous disease and are now in phase III of development. If progress continues and the preliminary results are confirmed, SC therapy will become a clinical reality in the near future. In this review we examine the basic concepts of the SC therapy, analyze the potential benefits of SCs in diseases of the digestive tract, and summarize current experience in the field and the future perspectives.     

Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy

Neurodegenerative diseases, such as Alzheimer's disease Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, share a common cellular and molecular pathogenetic mechanism involving aberrant misfolded protein or peptide aggregation and deposition. Autophagy represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Emerging studies have demonstrated that up-regulation of autophagy can lead to decreased levels of these toxic aggregate-prone proteins, and is beneficial in the context of aging and various models of neurodegenerative diseases. Understanding the signaling pathways involved in the regulation of autophagy is crucial to the development of strategies for therapy. This review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and neurodegenerative diseases, and the ongoing drug discovery strategies for therapeutic modulation.     

Stem cells and plasticity of skeletal muscle cell differentiation: potential application to cell therapy for degenerative muscular diseases

Degenerative muscular diseases, such as muscular dystrophies, have been the representative targets of regenerative cell therapy. Although satellite cells play central roles in skeletal muscle regeneration that intrinsically occurs after muscle injury, their application to cell therapy is confronted by difficulties. Other stem cells expected to be applicable to cell therapy include muscle-resident stem cells and nonmuscle-resident stem cells. Moreover, dedifferentiated cells of skeletal muscle might provide unique system for cell therapy. Terminally differentiated myotubes have plasticity of differentiation and dedifferentiate under certain experimental conditions, including the expression of SV40 large T antigen or the homeobox gene Msx1. The dedifferentiated cells exhibit multipotency to transdifferentiate into multiple mesenchymal origin cells. In addition, fibroblasts or undifferentiated myoblasts treated with a drug acquire multipotency. These cells may open new doors in cell therapy.     

干细胞治疗缺血性脑卒中的研究进展

背景：干细胞是一类种类多样,具有自我复制更新能力、多向分化潜能和高度增殖潜能的细胞,其治疗缺血性脑损伤将具有良好的前景。干细胞疗法为缺血性脑卒中的治疗提供了一种新的途径,但其机制尚不能完全明确。 目的：综述干细胞的类型及其治疗缺血性脑卒中机制的研究进展。 方法：第一作者应用计算机检索1992年1月至2012年9月PubMed数据库、中国期刊全文数据库有关干细胞分类及其移植治疗缺血性脑卒中疗效、安全性、机制方面的文章,英文检索词“stem cells,brain ischemic stroke,transplantation,treatment”;中文检索词“干细胞,缺血性脑卒中,移植,治疗”。共检索到168篇相关文献,61篇文献符合纳入标准。 结果与结论：虽然干细胞移植治疗脑卒中尚处于动物模型研究阶段,但已初步显示出其广阔的发展前景。多项干细胞移植治疗脑卒中促进功能恢复的临床Ⅰ期或Ⅱ期试验已经完成。干细胞移植治疗缺血性脑卒中的实验病例没有出现不良反应并显示出功能促进效果。干细胞移植治疗缺血性脑卒中存在的主要问题包括干细胞的来源、移植途径、干细胞在宿主体内存活及与宿主脑的整合问题、治疗的有效性以及安全性等。面对已经取得的一些机制研究和临床试验结果,如何安全而迅速地将治疗缺血性脑卒中的干细胞疗法从实验推向临床,仍然是需要努力的方向。     

Stem cell therapy for demyelinating disorders

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that attacks mainly young people. It leads to the progressive deterioration of the neurological status. Histopatologically, this disease is characterized by appearance of multiple foci of the demyelination in white matter of the CNS, with various grade of an axonal loss. The current treatment is targeted on moderating the inflammatory process and symptomatic therapy. In spite of all this therapy, the course of the disease often progresses. The tissue of the CNS in mammalians, including humans, is able to provide some degree of spontaneous remyelination. Unfortunatelly the extent of this process is not sufficient for the complete restoration. The support of remyelination by using the cell manipulations is the aim of many experimental studies. Theoretically, it is possible to achieve remyelination either by exogenous induction of remyelination from endogenous sources (precursor cells) or by the real transplantation of myelin-forming cells intrafocally, intracerebroventricularly or into the blood stream. In this work, we present the brief view on the recent state of this topic. We present the list of the cell types, useable for cell transplantations and the summary of the growth factors influencing the behaviour of the oligodendroglial precursors. We are considering the hampers in usage of the cell therapy of demyelinating disorders in clinics.     

Stem cell therapy: a hope for dying hearts

The restoration of functional myocardium following heart failure still remains a formidable challenge among researchers. Irreversible damage caused by myocardial infarction is followed by left ventricular remodeling. The current pharmacologic and interventional strategies fail to regenerate dead myocardium and are usually insufficient to meet the challenge caused by necrotic cardiac myocytes. There is growing evidence, suggesting that the heart has the ability to regenerate through the activation of resident cardiac stem cells or through the recruitment of a stem cell population from other tissues such as bone marrow. These new findings belie the earlier conception about the poor regenerating ability of myocardial tissue. Stem cell therapy is a promising new approach for myocardial repair. However, it has been limited by the paucity of cell sources for functional human cardiomyocytes. Moreover, cells isolated from different sources exhibit idiosyncratic characteristics including modes of isolation, ease of expansion in culture, proliferative ability, characteristic markers, etc., which are the basis for several technical manipulations to achieve successful engraftment. Clinical trials show some evidence for the successful integration of stem cells of extracardiac origin in adult human heart with an improved functional outcome. This may be attributed to the discrepancies in the methods of detection, study subject selection (early or late post transplantation), presence of inflammation, and false identification of infiltrating leukocytes. This review discusses these issues in a comprehensive manner so that their physiological significance in animal as well as in human studies can be better understood.     

干细胞治疗缺血性心脏病

BACKGROUND: Stem cell transplantation is a promising strategy for treatment of ischemic heart diseases, which has obtained great achievements in recent years. OBJECTIVE: To analyze the clinical trends of stem cell therapy for ischemic heart diseases reported from 2001 to 2015 in Medline, CNKI, Wanfang, ClinicalTrials.gov and Chinese Clinical Trial Register. METHODS: The relevant articles addressing stem cell therapy for ischemic heart diseases were retrieved using the keywords of “stem cell transplantation” and “ischemic heart disease” in Chinese and English in Medline, CNKI, Wanfang, ClinicalTrials.gov and Chinese Clinical Trial Register followed by statistical analysis. The retrieval time was from 2001 to 2015, including 2001-2005, 2006-2010 and 2011-2015. RESULTS AND CONCLUSION: In Medline database, there were 219 clinical studies about stem cell therapy for ischemic heart disease published from 2001 to 2015, and the number of retrieved articles was most from 2006 to 2010, and decreased from 2011 to 2015. In CNKI and Wanfang databases, the number of relevant articles which had a similar trend with that in the Medline database decreased remarkably after 2011. In ClinicalTrials.gov, there were 63 clinical trials about stem cell therapy for ischemic heart disease, most of which were registered from 2006 to 2015 and came from Europe and North America. In Chinese Clinical Trial Register, there was no clinical trial about stem cell therapy for ischemic heart disease, which may result from the strict management in China.      

下肢严重缺血的干细胞移植治疗

背景：近年来研究发现干细胞移植疗法由于能增加新血管生成,促进侧支循环的建立,故有望成为严重下肢缺血的有效治疗措施,但少有文献就此方面进行综述和概括。 目的：综述近年关于干细胞移植治疗下肢严重缺血的最新进展。 方法：应用计算机检索2010-10/2011-01 CNKI、PubMed数据库相关文章,检索词“肢体缺血,干细胞移植,血管新生,peripheral arterial disease,stem cells transplantation,neovascularzation”。共检索到文献68篇,最终纳入符合标准的文献24篇。 结果与结论：严重下肢缺血是外周动脉疾病的终末期,对患者的生活质量产生很大影响,其中一部分患者已经失去血管重建的机会。干细胞移植疗法由于能增加新血管生成,促进侧支循环建立,从而成为严重下肢缺血患者保肢的新选择而备受关注。但其潜在的新血管生成机制尚需通过基础研究和临床大宗随机对照研究来进一步完善,以期使更多的下肢严重缺血患者受益。     

Stem cell therapy for erectile dysfunction: a critical review

Erectile dysfunction (ED) is a prevailing health problem that seriously impacts quality of life. Current treatment options are less effective for patients having cavernous nerve (CN) injury or diabetes mellitus-related ED. These 2 types of ED are thus the main focus of past and current stem cell (SC) therapy studies. In a total of 16 studies so far, rats were exclusively used as disease models and SCs were mostly derived from bone marrow, adipose tissue, or skeletal muscle. For tracking, SCs were labeled with LacZ, green fluorescent protein, 4',6-diamidino-2-phenylindole, DiI, bromodeoxyuridine, or 5-ethynyl-2-deoxyuridine, some of which might have led to data misinterpretation. SC transplantation was done exclusively by intracavernous (IC) injection, which has been recently shown to have systemic effects. Functional assessment was done exclusively by measuring increases of IC pressure during electrostimulation of CN. Histological assessment usually focused on endothelial, smooth muscle, and CN contents in the penis. In general, favorable outcomes have been obtained in all trials so far, although whether SCs had differentiated into specific cell lineages remains controversial. Recent studies have shown that intracavernously injected SCs rapidly escaped the penis and homed into bone marrow. This could perhaps explain why intracavernously injected SCs had systemic antidiabetic effects and prolonged anti-ED effects. These hypotheses and the differentiation-versus-paracrine debate require further investigation.     

Stem cell therapy delivery: treading the regulatory tightrope

The concept of stem cell therapy has engaged the attention of the public and scientists alike. Intensive research effort is focused upon understanding the biology and therapeutic potential of embryonic and adult stem cells, with the eventual goal of treating such pathologies as Parkinson's disease, diabetes, neurological injury and degenerations and cancer. Ex vivo expansion and transplantation of limbal epithelial stem cells to the corneas to treat blinding ocular surface disease was one of the first stem cell therapies to successfully reach the clinic. However, limbal epithelial stem cell research and therapy delivery has remained largely within the noncommercial academic clinician-scientist environment from which it was originally pioneered. In our experience, gaining regulatory approval has been as great a hurdle as surmounting the scientific challenges of stem cell therapy. Based upon our model of delivering 'accredited' limbal epithelial stem cell therapy to patients in compliance with Good Manufacturing Practice and the new European Union Tissues and Cells Directive, we address the key regulatory questions. This may help colleagues who are developing innovative academic research-driven stem cell therapies regarding donor consent, raw materials, quality assurance, laboratory specification, indemnity and funding.     

Aging: An important factor for the pathogenesis of neurodegenerative diseases

Aging is a natural process that is defined as a progressive deterioration of biological functions after the organism has attained its maximal reproductive competence. Aging leads to the accumulation of disabilities and diseases that limit normal body functions and is a major risk factor for neurodegenerative diseases. Many neurodegenerative diseases share oxidative stress and nitrosative stress as common terminal processes. According to free radical theory of aging, an elevation in reactive oxygen species (ROS) and reactive nitrogen species (RNS) damages neural membranes and induces oxidative and nitrosative stress. The increase in oxidative and nitrosative stress is accompanied by the concomitant decline in cognitive and motor performance in the elderly population, even in the absence of neurodegenerative diseases. Markedly increased rates of oxidative and nitrosative stress are the major factors associated with the pathogenesis of neurodegenerative diseases. Diet is a key environmental factor that affects the incidence of chronic neurodegenerative diseases. Dietary supplementation with polyphenols, resveratrol, ginkgo biloba, curcumin, ferulic acid, carotenoids, flavonoids, and n-3 fatty acids exerts beneficial effects not only through the scavenging of free radicals, but also by modulating signal transduction, gene expression, and restoring optimal neuronal communication.     

Braingrafts: Potential therapy in neurodegenerative diseases and in understanding normal aging in the CNS

In addition to potentially improving the symptoms and the course of certain neurodegenerative diseases, brain tissue grafts may have even greater importance in the study of factors that lead to age-related alterations in the brain. Several strategies for studying this possibility are discussed.