Modelling mitochondrial dysfunction in Alzheimer's disease using human induced pluripotent stem cells

Alzheimer's disease(AD) is the most common form of dementia. To date, only five pharmacological agents have been approved by the Food and Drug Administration for clinical use in AD, all of which target the symptoms of the disease rather than the cause. Increasing our understanding of the underlying pathophysiology of AD will facilitate the development of new therapeutic strategies. Over the years, the major hypotheses of AD etiology have focused on deposition of amyloid beta and mitochondrial dysfunction. In this review we highlight the potential of experimental model systems based on human induced pluripotent stem cells(iPSCs) to provide novel insights into the cellular pathophysiology underlying neurodegeneration in AD. Whilst Down syndrome and familial AD iPSC models faithfully reproduce features of AD such as accumulation of Aβ and tau, oxidative stress and mitochondrial dysfunction,sporadic AD is much more difficult to model in this way due to its complex etiology. Nevertheless, iPSC-based modelling of AD has provided invaluable insights into the underlying pathophysiology of the disease, and has a huge potential for use as a platform for drug discovery.     

Pluripotent Stem Cells Models for Huntington＇s Disease： Prospects and Challenges

Pluripotent cellular models have shown great promise in the study of a number of neurological disorders.Several advantages of using a stem cell model include the potential for cells to derive disease relevant neuronal cell types,providing a system for researchers to monitor disease progression during neurogenesis,along with serving as a platform for drug discovery.A number of stem cell derived models have been employed to establish in vitro research models of Huntington’s disease that can be used to investigate cellular pathology and screen for drug and cell-based therapies.Although some progress has been made,there are a number of challenges and limitations that must be overcome before the true potential of this research strategy is achieved.In this article we review current stem cell models that have been reported,as well as discuss the issues that impair these studies.We also highlight the prospective application of Huntington’s disease stem cell models in the development of novel therapeutic strategies and advancement of personalized medicine.     

Use of human pluripotent stem cells to study and treat retinopathies

Human cell types affected by retinal diseases(such as age-related macular degeneration or retinitis pimentosa) are limited in cell number and of reduced accessibility. As a consequence, their isolation for in vitro studies of disease mechanisms or for drug screening efforts is fastidious. Human pluripotent stem cells(h PSCs), either of embryonic origin or through reprogramming of adult somatic cells,represent a new promising way to generate models of human retinopathies, explore the physiopathological mechanisms and develop novel therapeutic strategies. Disease-specific human embryonic stem cells were the first source of material to be used to study certain disease states. The recent demonstration that human somatic cells, such as fibroblasts or blood cells, can be genetically converted to induce pluripotent stem cells together with the continuous improvement of methods to differentiate these cells into disease-affected cellular subtypes opens new perspectives to model and understand a large number of human pathologies, including retinopathies. This review focuses on the added value of h PSCs for the disease modeling of human retinopathies and the study of their molecular pathological mechanisms. We also discuss the recent use of these cells for establishing the validation studies for therapeutic intervention and for the screening of large compound libraries to identify candidate drugs.     

Induced Pluripotency for Translational Research

The advent of induced pluripotent stem cells （iPSCs） has revolutionized the concept of cellular reprogramming and potentially will solve the immunological compatibility issues that have so far hindered the application of human pluripotent stem cells in regenerative medicine. Recent findings showed that pluripotency is defined by a state of balanced lineage potency, which can be artificially instated through various procedures, including the conventional Yamanaka strategy. As a type of pluripotent stem cell, iPSCs are subject to the usual concerns over purity of differen- tiated derivatives and risks of tumor formation when used for cell-based therapy, though they pro- vide certain advantages in translational research, especially in the areas of personalized medicine, disease modeling and drug screening, iPSC-based technology, human embryonic stem cells （hESCs） and direct lineage conversion each will play distinct roles in specific aspects of translational medi- cine, and continue yielding surprises for scientists and the public.     

Towards Personalized Intervention for Alzheimer’s Disease

Alzheimer’s disease (AD) remains to be a grand challenge for the international commu-nity despite over a century of exploration. A key factor likely accounting for such a situation is the vast heterogeneity in the disease etiology, which involves very complex and divergent pathways. Therefore, intervention strategies shall be tailored for subgroups of AD patients. Both demographic and in-depth information is needed for patient stratification. The demographic information includes primarily APOE genotype, age, gender, education, environmental exposure, life style, and medical history, whereas in-depth information stems from genome sequencing, brain imaging, peripheral biomarkers, and even functional assays on neurons derived from patient-specific induced pluripo-tent cells (iPSCs). Comprehensive information collection, better understanding of the disease mech-anisms, and diversified strategies of drug development would help with more effective intervention in the foreseeable future.     

Biomarkers for Primary Sjgren's Syndrome

Primary Sjo¨gren's syndrome(p SS) is a systemic autoimmune disease with exocrine gland dysfunction and multi-organ involvement. Recent progress in understanding the pathogenesis of p SS offers an opportunity to find new biomarkers for the diagnosis and assessment of disease activity. Screening noninvasive biomarkers from the saliva and tears has significant potential. The need for specific and sensitive biomarker candidates in p SS is significant. This review aims to summarize recent advances in the identification of biomarkers of Sjo¨gren syndrome, trying to identify reliable, sensitive, and specific biomarkers that can be used to guide treatment decisions.     

Disease Biomarkers for Precision Medicine: Challenges and Future Opportunities

<正>Most of the human diseases are complex diseases,which could be caused by many genetic pathways.This means that for a given phenotype(i.e.,a complex disease),there are multiple potential genes which could be genomically or epigenetically changed(i.e.,mutations,copy number variations,epigenetic modifications,and so on).Therefore,it is understandable that different individuals who share the same phenotype/diseases may have different causal genes and thus,may have different drug targets.For example,mutated genes are rarely common between the cancer patients of the same cancer type[1];furthermore,for a given drug,only 10%-30% of the patients     

Issues and opportunities of stem cell therapy in autoimmune diseases

The purpose of regenerative medicine is to restore or enhance the normal function of human cells, tissues, and organs. From a clinical point of view, the use of stem cells is more advantageous than differentiated cells because they can be collected more easily and in larger quantities, their proliferation capacity is more pronounced, they are more resistant in cell culture, their aging is delayed, they are able to form a number of cell lines, and they are able to promote vascularization of tissue carriers. The therapeutic use of stem cells for disease modification, immunomodulation, or regenerative purposes are undoubtedly encouraging, but most studies are still in their early stages, and the clinical results reported are not clear with regard to therapeutic efficacy and potential side effects. Uniform regulation of the clinical application of stem cells is also indispensable for this highly customizable, minimally invasive, individualized therapeutic method to become a successful and safe treatment alternative in many different autoimmune and autoinflammatory disorders.     

An Integrated Approach to Crop Genetic Improvement

The balance between the supply and demand of the major food crops is fragile,fueling concerns for long-term global food security.The rising population,increasing wealth and a proliferation of nonfood uses(e.g.bioenergy) has led to growing demands on agriculture,while increased production is limited by greater urbanization,and the degradation of land.Furthermore,global climate change with increasing temperatures and lower,more erratic rainfall is projected to decrease agricultural yields.There is a predicted need to increase food production by at least 70% by 2050 and therefore an urgent need to develop novel and integrated approaches,incorporating high-throughput phenotyping that will both increaseproduction per unit area and simultaneously improve the resource use efficiency of crops.Yield potential,yield stability,nutrient and water use are all complex multigenic traits and while there is genetic variability,their complexity makes such traits difficult to breed for directly.Nevertheless molecular plant breeding has the potential to deliver substantial improvements,once the component traits and the genes underlying these traits have been identified.In addition,interactions between the individual traits must also be taken into account,a demand that is difficult to fulfill with traditional screening approaches.Identified traits will be incorporated into new cultivars using conventional or biotechnological tools.In order to better understand the relationship between genotype,component traits,and environment over time,a multidisciplinary approach must be adopted to both understand the underlying processes and identify candidate genes,QTLs and traits that can be used to develop improved crops.     

Liver engraftment potential of hepatic cells derived from patient-specific induced pluripotent stem cells

Human induced pluripotent stem cells (iPSCs) are potential renewable sources of hepatocytes for drug development and cell therapy. Differentiation of human iPSCs into different developmental stages of hepatic cells has been achieved and improved during the last several years. We have recently demonstrated the liver engraftment and regenerative capabilities of human iPSC-derived multistage hepatic cells in vivo. Here we describe the in vitro and in vivo activities of hepatic cells derived from patientspecific iPSCs, including multiple lines established from either inherited or acquired liver diseases, and discuss basic and clinical applications of these cells for disease modeling, drug screening and discovery, gene therapy and cell replacement therapy.Key words: induced pluripotent stem cells (iPSCs), hepatic differentiation, liver ngraftment, disease modeling, drug testing, alpha-1 antitrypsin, liver cirrhosis, hepatocellular carcinoma, cell therapy     

Impact of induced pluripotent stem cells on the study of central nervous system disease

The derivation of pluripotent stem cells from somatic tissues has provided researchers with a source of patient-specific stem cells. The potential applications of this technology are truly momentous, and include cellular modeling of disease processes, drug discovery, and cell-based therapy. Here, we review the use of induced pluripotent stem cells (iPSCs) to study CNS disease. Since the iPSC field is still in its infancy, we also discuss some of the challenges that will need to be overcome before the potential of this technology to study and to treat neurological and psychiatric disorders can be fully harnessed.     

Liver engraftment potential of hepatic cells derived from patient-specific induced pluripotent stem cells

Human induced pluripotent stem cells (iPSCs) are potential renewable sources of hepatocytes for drug development and cell therapy. Differentiation of human iPSCs into different developmental stages of hepatic cells has been achieved and improved during the last several years. We have recently demonstrated the liver engraftment and regenerative capabilities of human iPSC-derived multistage hepatic cells in vivo. Here we describe the in vitro and in vivo activities of hepatic cells derived from patient specific iPSCs, including multiple lines established from either inherited or acquired liver diseases, and discuss basic and clinical applications of these cells for disease modeling, drug screening and discovery, gene therapy and cell replacement therapy.     

iPS cells: a game changer for future medicine

The induced pluripotent stem cell (iPSC) technology is instrumental in advancing the fields of disease modeling and cell transplantation. We herein discuss the various issues regarding disease modeling and cell transplantation presented in previous reports, and also describe new iPSC‐based medicine including iPSC clinical trials. In such trials, iPSCs from patients can be used to predict drug responders/non‐responders by analyzing the efficacy of the drug on iPSC‐derived cells. They could also be used to stratify patients after actual clinical trials, including those with sporadic diseases, based on the drug responsiveness of each patient in the clinical trials. iPSC‐derived cells can be used for the identification of response markers, leading to increased success rates in such trials. Since iPSCs can be used in micromedicine for drug discovery, and in macromedicine for actual clinical trials, their use would tightly connect both micro‐ and macromedicine. The use of iPSCs in disease modeling, cell transplantation, and clinical trials could therefore lead to significant changes in the future of medicine.     

Small Molecule Screening in Human Induced Pluripotent Stem Cell-derived Terminal Cell Types

A need for better clinical outcomes has heightened interest in the use of physiologically relevant human cells in the drug discovery process. Patient-specific human induced pluripotent stem cells may offer a relevant, robust, scalable, and cost-effective model of human disease physiology. Small molecule high throughput screening in human induced pluripotent stem cell-derived cells with the intent of identifying novel therapeutic compounds is starting to influence the drug discovery process; however, the use of these cells presents many high throughput screening development challenges. This technology has the potential to transform the way drug discovery is performed.     

Applications of patient-specific induced pluripotent stem cells; focused on disease modeling, drug screening and therapeutic potentials for liver disease

The recent advances in the induced pluripotent stem cell (iPSC) research have significantly changed our perspectives on regenerative medicine by providing researchers with a unique tool to derive disease-specific stem cells for study. In this review, we describe the human iPSC generation from developmentally diverse origins (i.e. endoderm-, mesoderm-, and ectoderm- tissue derived human iPSCs) and multistage hepatic differentiation protocols, and discuss both basic and clinical applications of these cells including disease modeling, drug toxicity screening/drug discovery, gene therapy and cell replacement therapy.     

诱导型多能干细胞iPSc研究现状及其移植治疗帕金森综合症应用前景

诱导多能干细胞(i PS细胞)在小鼠和人上的成功获取,使干细胞领域的研究进入了一个崭新的时代。干细胞研究是再生医学的重要组成部分,研究干细胞的最终目的是应用干细胞治疗疾病,其在疾病模型建立、药物筛选、细胞移植等方面具有极大的应用潜力。i PSCs是由体细胞诱导分化而成的"多能细胞",具备和胚胎干细胞类似的功能,既解决了ESCs的伦理障碍,又为ESCs的获得提供了一条全新的途径,具有重要的理论和应用价值。i PS细胞不仅打破了道德理论的束缚,而且在再生医学、组织工程和药物发现及评价等方面具有积极的价值。神经系统遗传性疾病发病率居各系统遗传病之首,但其发病的分子机制仍不完全清楚,运用体细胞重编程技术建立的疾病特异性诱导多能干细胞模型将有助于揭示神经系统遗传性疾病的发病机理。近几年i PS细胞最新研究成果表明,利用疾病患者i PS细胞模型已逐渐应用于帕金森氏病、老年性痴呆症、脊髓侧索硬化症、脊髓肌肉萎缩症及舞蹈症等5种常见神经性退行性疾病发病机理的研究。本文主要对i PSc的发展历程,避免病毒基因干扰诱导i PS细胞进行的优化,以及干细胞尤其是i PS细胞移植治疗帕金森病等神经系统疾病的现状及应用前景进行系统阐述与论证。