肺干细胞研究进展

干细胞研究是现代医学领域研究热点之一.肺部疾病所导致的不同程度呼吸系统病理改变和功能受损,都伴随着肺组织的修复和重塑过程.对于肺部疾病的干细胞研究和应用尚有许多问题有待进一步的明确和探索.肺干细胞包括了肺组织自身的干细胞修复和肺外组织来源的干细胞修复.肺组织内的干细胞包括肺内上皮性干细胞、肺问充质干细胞、肺侧群细胞;其中肺内上皮性干细胞又包括了基底细胞、Clara细胞、Ⅱ型肺泡上皮细胞、"芽孢"样细胞.肺外组织来源的干细胞修复包括骨髓间充质干细胞和造血干细胞.干细胞治疗方法在临床上有巨大的应用前景.     

肺损伤与干细胞修复

肺损伤的修复一直困扰着人类,人们一直试图寻找更新、更有效的治疗手段.细胞替代及基因治疗可能是理想的治疗策略,用干细胞分化成肺上皮细胞,作为基因治疗的靶点或器官再生与修复供源,替代病损的肺组织,减少肺纤维组织增生,进而逐渐修复病变肺组织,改善肺功能.目前,与肺损伤修复相关的干细胞主要有肺源性干细胞和骨髓源性干细胞.本文主要对肺损伤与干细胞修复作一简要综述.     

干细胞与肺损伤修复

肺脏是人体的重要器官,各种生物、物理和化学因素都能够引起肺损伤。肺损伤修复与干细胞功能密切相关。干细胞是一种具有多分化潜能及自我复制能力的早期未分化细胞。干细胞可分为三种类型：（1）全能干细胞：它具有形成完整个体的分化潜能。如胚胎干细胞;（2）多能干细胞：这种干细胞失去了发育成完整个体的能力,但具有分化出多种细胞组织的潜能。如骨髓造血干细胞和骨髓间充质干细胞;（3）单能干细胞：只能向一种类型或密切相关的两种类型的细胞分化,如上皮组织基底层的干细胞、肌肉中的成肌细胞。与肺组织损伤修复有关的干细胞包括肺内干细胞和骨髓干细胞。     

干细胞诱导分化肺组织的研究进展

干细胞研究是现代医学和生物学领域最大的研究热点之一。尤其近20年来在干细胞应用上已取得初步进展。干细胞可在体内外分化为各种类型的组织细胞，并修复那些不能再生或修复缓慢的组织和器官，进而治疗现在很多无法根治的疾病。胸科领域中心肌梗死患者的干细胞技术应用即是极为有效的临床实例。目前对于肺部疾病中的干细胞应用仅属初步阶段。肺部疾病所致的肺功能不可逆性下降、以致终末期肺损害已占我国致死疾患的3．17％，相比之下可供采用的治疗手段有限、疗效欠佳，即使施行异体肺移植，远期效果亦欠满意。干细胞技术在该领域的基础研究和临床应用前景已成为肺科学者关注的热点之一。以下就近10年干细胞在肺组织分化方面的研究情况作一综述。     

干细胞治疗肺部疾病的研究进展

目前,干细胞治疗包括ARDS、矽肺、肺气肿和支气管哮喘在内的肺部疾病的实验方面已经取得了良好的疗效,而测试干细胞疗法安全性和有效性的临床试验亦正在进行中.本文着重阐述了干细胞对肺部疾病损伤的修复及其在肺疾病治疗中的应用前景和存在的问题.     

急性肺损伤干细胞修复的研究进展

急性肺损伤/急性呼吸窘迫综合征的重要病理改变是肺泡上皮损伤,进而引起肺泡-毛细血管膜的损伤,出现气体弥散障碍。肺内自身存在及肺外组织来源的干细胞在肺损伤时可分化为上皮细胞,修复损伤肺组织的结构和功能,发挥治疗作用。本文就近年来国外对这方面的研究作一综述。     

间充质干细胞与肺疾病的研究进展

间充质干细胞(mesenchymal stem cells,MSC)是一类具有自我复制和多向分化潜能的成体干细胞,广泛分布于人及动物多种组织和器官中.文献报道MSC在体内能分化为气道及肺组织上皮细胞.本文着重阐述了MSC对肺疾病损伤的修复及其在肺疾病治疗中的应用前景和存在的问题.     

间充质干细胞来源微粒及其在肺脏疾病中的研究进展

间充质干细胞来源的微粒是间充质干细胞在静息或活化状态下释放到细胞外基质中直径30～1 000 nm的膜性小囊泡.最近的研究发现干细胞来源的微粒可以有效地转运mRNA、miRNA和蛋白质等生物活性物质,在调控组织再生修复方面发挥重要作用.本文综述干细胞微粒的形成机制、生物学特性及在肺脏疾病中主要作用的研究进展,为干细胞肺组织修复机制研究提供新的思路.     

干细胞与呼吸系统疾病

干细胞（stem cell）是组织器官的起源细胞，近年来对于细胞的研究结果显示，干细胞在组织器官修复、发育生物学、遗传性疾病、药物学等多个生命学科有着广泛的应用前景，但由于呼吸系统解剖以及功能的复杂性，呼吸系统干细胞的研究相对滞后。对呼吸系统干细胞的研究，不仅可以对肺的发育、肺损伤修复机制有一个新的认识，而且对肺损伤修复治疗的设计也有重要意义。现将呼吸系统干细胞相关研究进展综述如下。     

人胚肺间充质干细胞对损伤肺组织的修复作用

目的 研究人胚肺间充质干细胞(MSCs)对损伤肺组织的修复作用.方法 通过动物体内实验和细胞体外培养实验,观察人MSCs对肺上皮细胞的生长调控.结果 人胚肺MSCs能有效调控肺泡上皮的生长.结论 人胚肺MSCs及其条件培养液可以减轻人肺上皮损伤和加速修复,从而为临床治疗COPD、病毒性肺炎造成的肺损伤提供新的生物治疗方法.     

Adult stem cells for chronic lung diseases

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are chronic, progressive and lethal lung diseases. The incidence of IPF and COPD increases with age, independent of exposure to common environmental risk factors. At present, there is limited understanding of the relationship between ageing and the development of chronic lung diseases. One hypothesis is that chronic injury drives to exhaustion the local and systemic repair responses in the lung. These changes are accentuated during ageing where there is a progressive accumulation of senescent cells. Recently, stem cells have emerged as a critical reparative mechanism for lung injury. In this review, we discuss the repair response of bone marrow‐derived mesenchymal stem cells (B‐MSC) after lung injury and how their function is affected by ageing. Our own work has demonstrated a protective role of B‐MSC in several animal models of acute and chronic lung injury. We recently demonstrated the association, using animal models, between age and an increase in the susceptibility to develop severe injury and fibrosis. At the same time, we have identified functional differences between B‐MSC isolated from young and old animals. Further studies are required to understand the functional impairment of ageing B‐MSC, ultimately leading to a rapid stem cell depletion or fatigue, interfering with their ability to play a protective role in lung injury. The elucidation of these events will help in the development of rational and new therapeutic strategies for COPD and IPF.     

Mesenchymal stem cells and the lung

Mesenchymal stem cells (MSC) are a population of tissue‐resident adult progenitor cells that were originally identified in bone marrow, but have now been identified in many organs including the lung. Although their precise role in organ function remains incompletely defined, mounting evidence suggests that they are an important component of the parenchymal progenitor cell niche and orchestrate organ homeostasis and repair following injury. In this review, what is known about MSC biology will be outlined with particular emphasis on lung biology, and the therapeutic potential of MSC‐based cell therapy will also be highlighted.     

骨髓间充质干细胞治疗急性肺损伤/急性呼吸窘迫综合征的研究进展

急性肺损伤/急性呼吸窘迫综合征是临床危重症之一,目前尚无特效疗法.骨髓间充质干细胞是多分化潜能的干细胞,可以归巢至肺脏并长期地定植,通过诱导分化,进行组织修复.骨髓间充质干细胞在受到损伤时释放,分泌大量免疫和营养相关的生物活性因子.在免疫调节中,抑制受损组织的淋巴细胞的免疫监视,逃避自身免疫,是异基因骨髓间充质干细胞广泛运用于临床治疗的基础,为急性肺损伤急性呼吸窘迫综合征的治疗提供新思路.     

Autologous cell‐based therapy for ischemic heart disease: Clinical evidence,proposed mechanisms of action,and current limitations

Cell‐based therapy is a promising approach for cardiac repair in patients with coronary artery disease. In preclinical and early clinical studies, investigators have preliminary evidence showing that stem cell therapy can safely and effectively improve myocardial perfusion and left ventricular function. Cardiac stem cell therapy may decrease left ventricular remodeling in cases of myocardial infarction and may alleviate symptoms and prevent cardiac enlargement in chronic ischemic heart disease. Various mechanisms, including paracrine effects, are believed to contribute to stem cell‐mediated cardiac repair. Further studies are needed to determine the optimal timing of therapy, best mode of delivery, and most effective cell dose. Cardiac stem cell therapy promises to become an important option for treating patients with coronary artery disease. © 2009 Wiley‐Liss, Inc.     

Stem/progenitor cells in lung development, injury repair, and regeneration

At least two populations of epithelial stem/progenitor cells give rise to the lung anlage, comprising the laryngo-tracheal complex versus the distal lung below the first bronchial bifurcation. Amplification of the distal population requires FGF9-FGF10-FGFR2b-Sprouty signaling. Residual pools of adult stem cells are hypothesized to be the source of lung regeneration and repair. These pools have been located within the basal layer of the upper airways, within or near pulmonary neuroendocrine cell rests, at the bronchoalveolar junction as well as within the alveolar epithelial surface. Rapid repair of the denuded alveolar surface after injury is clearly key to survival. Strategies to enhance endogenous alveolar epithelial repair could include protection of epithelial progenitors from injury and/or stimulation of endogenous progenitor cell function. Protection with inosine or FGF signaling are possible small molecule therapeutic options. Alternatively, exogenous stem/progenitor cells can be delivered into the lung either intravenously, intratracheally, or by direct injection. Sources of exogenous stem/progenitor cells that are currently under evaluation in the context of acute lung injury repair include embryonic stem cells, bone marrow- or fat-derived mesenchymal stem cells, circulating endothelial progenitors, and, recently, amniotic fluid stem/progenitor cells. Further work will be needed to translate stem/progenitor cell therapy for the lung.     

From the Cover: Stem cells are dispensable for lung homeostasis but restore airways after injury

Local tissue stem cells have been described in airways of the lung but their contribution to normal epithelial maintenance is currently unknown. We therefore developed aggregation chimera mice and a whole-lung imaging method to determine the relative contributions of progenitor (Clara) and bronchiolar stem cells to epithelial maintenance and repair. In normal and moderately injured airways chimeric patches were small in size and not associated with previously described stem cell niches. This finding suggested that single, randomly distributed progenitor cells maintain normal epithelial homeostasis. In contrast we found that repair following severe lung injury resulted in the generation of rare, large clonal cell patches that were associated with stem cell niches. This study provides evidence that epithelial stem cells are dispensable for normal airway homeostasis. We also demonstrate that stem cell activation and robust clonal cellular expansion occur only during repair from severe lung injury.     

Rehabilitation for patients with myalgic encephalomyelitis/chronic fatigue syndrome: time to extent the boundaries of this field

The adult brain has a very limited capacity for generation of new neurons, and neurogenesis only takes place in restricted regions. Some evidence for neurogenesis after injury has been reported, but few, if any, neurons are replaced after brain injury or degeneration, and the permanent loss of neurons leads to long‐term disability and loss of brain function. For decades, researchers have been developing cell transplantation using exogenous cell sources for brain repair, and this method has now been shown to successfully restore lost function in experimental and clinical trials. Here, we review the development of cell‐replacement strategies for brain repair in Parkinson's disease using the example of human foetal brain cells being successfully translated from preclinical findings to clinical trials. These trials demonstrate that cell‐replacement therapy is a viable option for patients with Parkinson's disease, but more importantly also show how the limited availability of foetal cells calls for development of novel cell sources and methods for generating new neurons for brain repair. We focus on new stem cell sources that are on the threshold of clinical application for brain repair and discuss emerging cellular reprogramming technologies. Reviewing the current status of direct neural conversion, both in vitro and in vivo, where somatic cells are directly reprogrammed into functional neurons without passing through a stem cell intermediate, we conclude that both methods result in the successful replacement of new neurons that mature and integrate into the host brain. Thus, this new field shows great promise for future brain repair, although much work is still needed in preclinical animal models before it can be seriously considered for clinical applications.     

Rationale and emerging approaches for targeting lung repair and regeneration in the treatment of chronic obstructive pulmonary disease

Lung repair and regeneration are appropriate therapeutic targets for the treatment of chronic obstructive pulmonary disease (COPD). Abnormal repair results if fibrosis of the airways is a major contributor to fixed airflow limitation in airway disease. Inadequate repair in the face of tissue injury can contribute to the development of emphysema. With respect to the latter, acute exposure to cigarette smoke can impair repair responses of several cell types in the lung. Fibroblasts cultured from the lungs of patients with emphysema have persistent defects in repair that include modulation of extracellular matrix as well as production of growth factors that modulate other lung parenchymal cells. Some of the deficient repair functions appear to result from insensitivity to TGF-β and overproduction of prostaglandin E. Pharmacologic interventions targeting these pathways have the potential to at least partially reverse the abnormal repair. Alternate strategies that could modulate lung repair and regeneration could target resident or circulating stem/progenitor cells or potentially involve transplantation of new stem cells. Therapy directed at lung repair has the potential to restore lost lung function. In contrast to therapy designed to slow the progression of COPD, it may be much easier and less expensive to demonstrate efficacy for a therapy that restores lung function.