成体干细胞肺重建研究进展

成体干细胞来源广泛,无伦理争议,成为近几年的关注热点。研究表明以骨髓来源的间充质干细胞为代表的成体干细胞具有较强的多系分化潜能,可以广泛的参与包括肺在内的受损组织的修复与重建。在动物实验中已观察到,供体来源的成体干细胞可以定向分化为受损肺组织的多种功能细胞,并且有抑制纤维化等病变产生的能力。在本文中,回顾了近年来与肺损伤重建和疾病治疗相关的干细胞研究的最新进展,并探讨了成体干细胞治疗肺疾病与损伤的临床应用前景。     

Programmatic change: lung disease research in the era of induced pluripotency

Human lung research has made remarkable progress over the last century largely through the use of animal models of disease. The challenge for the future is to translate these findings into human disease and bring about meaningful disease modification or even cure. The ability to generate transformative therapies in the future will require human tissue, currently scarce under the best of circumstances. Unfortunately, patient-derived somatic cells are often poorly characterized and have a limited life span in culture. Moreover, these cells are frequently obtained from patients with end-stage disease exposed to multiple drug therapies, leaving researchers with questions about whether their findings recapitulate disease-initiating processes or are simply the result of pharmacological intervention or subsequent host responses. The goal of studying early disease in multiple cell and tissue types has driven interest in the use of induced pluripotent stem cells (iPSCs) to model lung disease. These cells provide an alternative model for relevant lung research and hold promise in particular for studying the initiation of disease processes in genetic conditions such as heritable pulmonary arterial hypertension as well as other lung diseases. In this Perspective, we focus on potential iPSC use in pulmonary vascular disease research as a model for iPSC use in many types of advanced lung disease.     

Stem cell therapy for COVID-19 and other respiratory diseases: Global trends of clinical trials

Respiratory diseases, including coronavirus disease 2019 and chronic obstructive pulmonary disease (COPD), are leading causes of global fatality. There are no effective and curative treatments, but supportive care only. Cell therapy is a promising therapeutic strategy for refractory and unmanageable pulmonary illnesses, as proved by accumulating preclinical studies. Stem cells consist of totipotent, pluripotent, multipotent, and unipotent cells with the potential to differentiate into cell types requested for repair. Mesenchymal stromal cells, endothelial progenitor cells, peripheral blood stem cells, and lung progenitor cells have been applied to clinical trials. To date, the safety and feasibility of stem cell and extracellular vesicles administration have been confirmed by numerous phase I/II trials in patients with COPD, acute respiratory distress syndrome, bronchial dysplasia, idiopathic pulmonary fibrosis, pulmonary artery hypertension, and silicosis. Five routes and a series of doses have been tested for tolerance and advantages of different regimes. In this review, we systematically summarize the global trends for the cell therapy of common airway and lung diseases registered for clinical trials. The future directions for both new clinical trials and preclinical studies are discussed.     

Notch signaling in the mammalian respiratory system,specifically the trachea and lungs,in development,homeostasis, regeneration,and disease

The respiratory system has ideal tissue structure and cell types for efficient gas exchange to intake oxygen and release carbon dioxide. This complex system develops through orchestrated intercellular signaling among various cell types, such as club, ciliated, basal, neuroendocrine, AT1, AT2, endothelial, and smooth muscle cells. Notch signaling is a highly conserved cell–cell signaling pathway ideally suited for very short-range cellular communication because Notch signals are transmitted by direct contact with an adjacent cell. Enthusiastic efforts by Notch researchers over the last two decades have led to the identification of critical roles of this signaling pathway during development, homeostasis, and regeneration of the respiratory system. The dysregulation of Notch signaling results in a wide range of respiratory diseases such as pulmonary artery hypertension (PAH), chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis (IPF), and lung cancer. Thus, a deep understanding of the biological functions of Notch signaling will help identify novel treatment targets in various respiratory diseases.     

Adult stem cells underlying lung regeneration

Despite the massive toll in human suffering imparted by degenerative lung disease, including COPD, idiopathic pulmonary fibrosis and ARDS, the scientific community has been surprisingly agnostic regarding the potential of lung tissue and, in particular, the alveoli, to regenerate. However, there is circumstantial evidence in humans and direct evidence in mice that ARDS triggers robust regeneration of lung tissue rather than irreversible fibrosis. The stem cells responsible for this remarkable regenerative process has garnered tremendous attention, most recently yielding a defined set of cloned human airway stem cells marked by p63 expression but with distinct commitment to differentiated cell types typical of the upper or lower airways, the latter of which include alveoli-like structures in vitro and in vivo. These recent advances in lung regeneration and distal airway stem cells and the potential of associated soluble factors in regeneration must be harnessed for therapeutic options in chronic lung disease.Key words: ARDs, lung regeneration, lung stem cells, influenza, COPD, pulmonary fibrosis     

Teeth-derived stem cells: A source for cell therapy

Cell therapy is one of the important therapeutic approaches in the treatment of many diseases such as cancer, degenerative diseases, and cardiovascular diseases. Among various cell types, which could be used as cell therapies, stem cell therapy has emerged as powerful tools in the treatment of several diseases. Multipotent stem cells are one of the main classes of stem cells that could originate from different parts of the body such as bone marrow, adipose, placenta, and tooth. Among several types of multipotent stem cells, tooth-derived stem cells (TDSCs) are associated with special properties such as accessible, easy isolation, and low invasive, which have introduced them as a good source for using in the treatment of several diseases such as neural injuries, liver fibrosis, and Cohrn’s disease. Here, we provided an overview of TDSCs particular stem cells from human exfoliated deciduous teeth and clinical application of them. Moreover, we highlighted molecular mechanisms involved in the regulation of dental stem cells fate.     

Adult stem cells underlying lung regeneration

Despite the massive toll in human suffering imparted by degenerative lung disease, including COPD, idiopathic pulmonary fibrosis and ARDS, the scientific community has been surprisingly agnostic regarding the potential of lung tissue, and in particular the alveoli, to regenerate. However, there is circumstantial evidence in humans and direct evidence in mice that ARDS triggers robust regeneration of lung tissue rather than irreversible fibrosis. The stem cells responsible for this remarkable regenerative process has garnered tremendous attention, most recently yielding a defined set of cloned human airway stem cells marked by p63 expression but with distinct commitment to differentiated cell types typical of the upper or lower airways, the latter of which include alveoli-like structures in vitro and in vivo. These recent advances in lung regeneration and distal airway stem cells and the potential of associated soluble factors in regeneration must be harnessed for therapeutic options in chronic lung disease.     

Paving the road for lung stem cell biology: bronchioalveolar stem cells and other putative distal lung stem cells

New discoveries in stem cell biology are making the biology of solid tissues increasingly complex. Important seminal studies demonstrating the presence of damage-resistant cell populations together with new isolation and characterization techniques suggest that stem cells exist in the adult lung. More detailed in vivo molecular and cellular characterization of bronchioalveolar stem cells (BASCs), other putative lung stem and progenitor cells, and differentiated cells is needed to determine the lineage relationships in adult lung. Lung diseases such as cystic fibrosis or chronic obstructive pulmonary disease, as well as the most common form of lung cancer in the United States, all involve apparent bronchiolar and alveolar cell defects. It is likely that the delicate balance of stem, progenitor, and differentiated cell functions in the lung is critically affected in patients with these devastating diseases. Thus the discovery of BASCs and other putative lung stem cells will lay the foundation for new inroads to understanding lung biology related to lung disease.     

干细胞生物工程研究展望

 由于最近两年干细胞研究技术的突破 ,一门崭新的学科“干细胞生物工程”已经形成 .人类胚胎干细胞在体外的成功培养以及一种组织的干细胞 (成体干细胞 )向另一种组织细胞横向分化的发现 ,为利用“干细胞生物工程”技术治疗疾病奠定了基础 .本综述着重介绍干细胞研究领域的一些新概念和新技术以及干细胞分化的基因调控 .对干细胞生物工程的临床应用前景作了概括性讨论     

Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis

Fibrotic interstitial lung diseases are characterized by progressive decline in lung function and premature death from respiratory failure. Fibrocytes are circulating bone marrow-derived progenitor cells that traffic to the lungs and contribute to fibrosis and may represent novel therapeutic targets in these diseases. We have previously found the recruitment of fibrocytes to the lung to be dependent on the chemokine ligand CXCL12. Given that the expression of the CXCL12 receptor, CXCR4, can be modulated pharmacologically in other cell types, we tested the hypotheses that the regulation of CXCR4 expression on fibrocytes mediates their influx to the lung in the context of pulmonary fibrosis and that pharmacologic inhibition of this process results in attenuated disease severity. CXCR4 was the predominant chemokine receptor on human fibrocytes, and its expression on fibrocytes was enhanced by hypoxia and by growth factors including platelet-derived growth factor. Both hypoxia-induced and growth factor-induced CXCR4 expressions were attenuated by specific inhibition of PI3-kinase and mTOR. Finally, in the mouse model of bleomycin-induced pulmonary fibrosis, treatment with the mTOR inhibitor rapamycin resulted in reduced numbers of CXCR4-expressing fibrocytes in the peripheral blood and lung as well as reduced lung collagen deposition. Taken together, these experiments support the notion that pharmacologic inhibition of the CXCR4/CXCL12 biological axis is achievable in human fibrocytes and reduces the magnitude of pulmonary fibrosis in an animal model. This approach may hold promise in human fibrotic lung diseases.     

Respiratory stem cells and progenitors: overview, derivation, differentiation, carcinogenesis, regeneration and therapeutic application

Recently, research of stem cells has garnered great attention and has shown promise by changing the view of traditional therapeutics, with broad impact on gene therapy, carcinogenesis, organ development, tissue injury, regeneration and almost all aspects of the life cycle and all living systems. A century's scientific progress has significantly improved controls for infectious diseases and many other disorders. However, many remaining problems (i.e. cancer, AIDS, diabetes, Parkinson's disease and Marburg infection) appear to be even harder than those that have already been solved. In particular, respiratory stem cell research has been less active and has moved more slowly than that of many other organs. This is probably due to the complexity of the lung and airway system, particularly owing to the many types of cells (>40), unique structures and functions, and technical difficulty in analyzing this system at the genetic, biochemical, molecular and cellular level. Compared with other epithelial cells (i.e., gastrointestinal epithelium), respiratory epithelia have a very low turnover rate and minimal regenerative activity. This review will discuss the current state of pulmonary stem cells, their origin, development, differentiation, and regenerative application, with a particular focus on potential impact on cancer development and lung injury repair.     

抗肺纤维化药物治疗研究进展

特发性肺纤维化是严重危害生命的间质性肺疾病,诊断后半数生存率仅为3年,超过大部分恶性肿瘤.目前所有的抗肺纤维化治疗措施疗效甚微.随着对肺纤维化发病分子细胞机制研究的不断深入,已经发现并确认多种抗肺纤维化的新药靶.本文首先概述抗肺纤维化疾病的临床治疗现状、正在临床实验的新药物,然后重点介绍作用于肺泡上皮细胞、成肌纤维细胞或具有抑制血管新生、调节Th1/Th2细胞因子平衡、阻断氧化应激等作用药物治疗肺纤维化疾病的前景.     

干细胞研究伦理

干细胞具有＂分化＂和＂脱分化＂的特点和潜能,干细胞研究有着良好的医学前景,许多人类严重疾病的治疗有了新的希望。伴随着干细胞研究的开展和深入,出现了诸多伦理问题的争论。拟就干细胞研究的希望和现实、伦理争论的主要观点及干细胞研究伦理准则的构建,作一简要介绍,并就加强干细胞管理提出建议。     

Impediment in upper airway stabilizing forces assessed by phrenic nerve stimulation in sleep apnea patients

Research into respiratory diseases has reached a critical stage and the introduction of novel therapies is essential in combating these debilitating conditions. With the discovery of the peroxisome proliferator-activated receptor and its involvement in inflammatory responses of cardiovascular disease and diabetes, attention has turned to lung diseases and whether knowledge of this receptor can be applied to therapy of the human airways. In this article, we explore the prospect of peroxisome proliferator-activated receptor-γ as a marker and treatment focal point of lung diseases such as asthma, chronic obstructive pulmonary disorder, lung cancer and cystic fibrosis. It is anticipated that peroxisome proliferator-activated receptor-γ ligands will provide not only useful mechanistic pathway information but also a possible new wave of therapies for sufferers of chronic respiratory diseases.     

Therapeutic effect of a peptide inhibitor of TGF-β on pulmonary fibrosis

Pulmonary fibrosis encompasses several respiratory diseases characterized by epithelial cell injury, inflammation and fibrosis. Transforming growth factor (TGF)-β1 is one of the main profibrogenic cytokines involved in the pathogenesis of lung fibrosis. It induces fibroblast differentiation into myofibroblasts, which produce high levels of collagen and concomitantly loss of lung elasticity and reduction of the respiratory function. In the present study, we have investigated the effects of P17 (a TGF-β inhibitor peptide) on IMR-90 lung fibroblast differentiation in vitro, as well as on the inhibition of the development of bleomycin-induced pulmonary fibrosis in mice. It was found that in IMR-90 cells, P17 inhibited TGF-β1-induced expression of connective tissue growth factor and α-smooth muscle actin. In vivo, treatment of mice with P17 2days after bleomycin administration decreased lung fibrosis, areas of myofibroblast-like cells and lymphocyte infiltrate. P17 also reduced mRNA expression of collagen type I, fibronectin and the fibronectin splice isoform EDA in the lung, and increased the expression of IFN-γ mRNA. Finally, therapeutic treatment with P17 in mice with already established fibrosis was able to significantly attenuate the progression of lung fibrosis. These results suggest that P17 may be useful in the treatment of pulmonary fibrosis.     

Pluripotent human stem cells for the treatment of retinal disease

Despite advancements made in our understanding of ocular biology, therapeutic options for many debilitating retinal diseases remain limited. Stem cell-based therapies are a potential avenue for treatment of retinal disease, and this mini-review will focus on current research in this area. Cellular therapies to replace retinal pigmented epithelium (RPE) and/or photoreceptors to treat age-related macular degeneration (AMD), Stargardt's macular dystrophy, and retinitis pigmentosa are currently being developed. Over the past decade, significant advancements have been made using different types of human stem cells with varying capacities to differentiate into these target retinal cell types. We review and evaluate pluripotent stem cells, both human embryonic stem cells and human induced pluripotent stem cells, as well as protocols for differentiation of ocular cells, and culture and transplant techniques that might be used to deliver cells to patients.     

The pathophysiological function of peroxisome proliferator-activated receptor-γ in lung-related diseases

Research into respiratory diseases has reached a critical stage and the introduction of novel therapies is essential in combating these debilitating conditions. With the discovery of the peroxisome proliferator-activated receptor and its involvement in inflammatory responses of cardiovascular disease and diabetes, attention has turned to lung diseases and whether knowledge of this receptor can be applied to therapy of the human airways. In this article, we explore the prospect of peroxisome proliferator-activated receptor-γ as a marker and treatment focal point of lung diseases such as asthma, chronic obstructive pulmonary disorder, lung cancer and cystic fibrosis. It is anticipated that peroxisome proliferator-activated receptor-γ ligands will provide not only useful mechanistic pathway information but also a possible new wave of therapies for sufferers of chronic respiratory diseases.     

Pluripotent plasticity of stem cells and liver repopulation

Different types of stem cells have a role in liver regeneration or fibrous repair during and after several liver diseases. Otherwise, the origin of hepatic and/or extra‐hepatic stem cells in reactive liver repopulation is under controversy. The ability of the human body to self‐repair and replace the cells and tissues of some organs is often evident. It has been estimated that complete renewal of liver tissue takes place in about a year. Replacement of lost liver tissues is accomplished by proliferation of mature hepatocytes, hepatic oval stem cells differentiation, and sinusoidal cells as support. Hepatic oval cells display a distinct phenotype and have been shown to be a bipotential progenitor of two types of epithelial cells found in the liver, hepatocytes, and bile ductular cells. In gastroenterology and hepatology, the first attempts to translate stem cell basic research into novel therapeutic strategies have been made for the treatment of several disorders, such as inflammatory bowel diseases, diabetes mellitus, celiachy, and acute or chronic hepatopaties. In the future, pluripotent plasticity of stem cells will open a variety of clinical application strategies for the treatment of tissue injuries, degenerated organs. The promise of liver stem cells lie in their potential to provide a continuous and readily available source of liver cells that can be used for gene therapy, cell transplant, bio‐artificial liver‐assisted devices, drug toxicology testing, and use as an in vitro model to understand the developmental biology of the liver. Copyright © 2010 John Wiley & Sons, Ltd.     

Current status of stem cell research: An editorial

The purpose of this editorial is to highlight recent developments in molecular biology tools and techniques in stem cell research and their applications to human diseases. Recent advancements in stem cell research and regenerative medicine are offering immense hope to cure human diseases and injuries, such as cancer, diabetes, Alzheimer's disease, Parkinson's disease, and traumatic brain injuries. In the last three decades, especially in the last decade, major breakthroughs have been seen in the conversion of adult stem cells into induced pluripotent stem cells, which in turn has led the way to developing stem cell therapies for human diseases. This article summarizes contributions of research into stem cell therapies.