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。     

Stem cells for lung cancer?

Stem cells are believed to be crucial players in tumor development. There is much interest in identifying those compartments that harbor stem cells involved in lung cancer, given the high incidence and recurrence rate of this disease. In this issue of Cell, Kim and colleagues describe a niche in the bronchioalveolar duct junction of adult mouse lung that harbors stem cells from which adenocarcinomas are likely to arise. They enriched, propagated, and differentiated these stem cells in vitro and found that they were activated by the oncogenic protein K-ras. This study provides exciting insights into how the stem cell compartment operates during both normal lung-tissue homeostasis and the development of lung cancer. The new work offers perspectives on possible therapeutic interventions to combat lung cancer.     

Lung stem cells

The lung is a relatively quiescent tissue comprised of infrequently proliferating epithelial, endothelial, and interstitial cell populations. No classical stem cell hierarchy has yet been described for the maintenance of this essential tissue; however, after injury, a number of lung cell types are able to proliferate and reconstitute the lung epithelium. Differentiated mature epithelial cells and newly recognized local epithelial progenitors residing in specialized niches may participate in this repair process. This review summarizes recent discoveries and controversies, in the field of stem cell biology, that are not only challenging, but also advancing an understanding of lung injury and repair. Evidence supporting a role for the numerous cell types believed to contribute to lung epithelial homeostasis is reviewed, and initial studies employing cell-based therapies for lung disease are presented. As a detailed understanding of stem cell biology, lung development, lineage commitment, and epithelial differentiation emerges, an ability to modulate lung injury and repair is likely to follow.     

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.     

Cell-based cardiovascular repair and regeneration in acute myocardial infarction and chronic ischemic cardiomyopathy-current status and future developments

Ischemic heart disease is the main cause of death and morbidity in most industrialized countries. Stem- and progenitor cell-based treatment approaches for ischemic heart disease are therefore an important frontier in cardiovascular and regenerative medicine. Experimental studies have shown that bone-marrow-derived stem cells and endothelial progenitor cells can improve cardiac function after myocardial infarction, clinical phase I and II studies were rapidly initiated to translate this concept into the clinical setting. However, as of now the effects of stem/progenitor cell administration on cardiac function in the clinical setting have not met expectations. Thus, a better understanding of causes of the current limitations of cell-based therapies is urgently required. Importantly, the number and function of endothelial progenitor cells is reduced in patients with cardiovascular risk factors and/or coronary artery disease. These observations may provide opportunities for an optimization of cell-based treatment approaches. This review provides a summary of current evidence for the role and potential of stem and progenitor cells in the pathophysiology and treatment of ischemic heart disease, including the properties, and repair and regenerative capacities of various stem and progenitor cell populations. In addition, we describe modes of stem/progenitor cell delivery, modulation of their homing as well as potential approaches to "prime" stem/progenitor cells for cardiovascular cell-based therapies.     

Human embryonic stem cells: emerging technologies and practical applications

Human embryonic stem cells possess the unique ability to differentiate into any adult cell type. Recent advances in the understanding of stem cell biology make new applications possible for stem cell based technology. Of note, it is now possible to reprogram terminally differentiated human somatic cells into pluripotent cells that are functionally equivalent to embryonic stem cells. These induced pluripotent cells may become the substrate for future disease models and cell-based therapies. In addition, novel techniques for genetic manipulation have increased the ease with which genes can be modified into stem cells. In this review, we describe these novel technologies as well as developments in the understanding of basic biology of stem cell pluripotency and differentiation.     

Wnt signaling in stem and cancer stem cells

Canonical Wnt signaling supports the formation and maintenance of stem and cancer stem cells. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment how embryonic and tissue stem cells are generated and maintained, and how Wnt signaling might be involved. The core of this review highlights the roles of Wnt signaling in stem and cancer stem cells of tissues such as skin, intestine and mammary gland. Lastly, we refer to the characterization of novel and powerful inhibitors of canonical Wnt signaling and describe attempts to bring these compounds into preclinical and clinical studies.     

Prostate stem cells and cancer

Properties shared by neoplastic and stem cells indicate a possibility that somatic stem cells or transit-amplifying cells that have reacquired stem cell properties, particularly the ability for self-renewal, represent favorable targets for malignant transformation. In this review we discuss significance of the stem cell model for understanding prostate cancer pathogenesis and describe relevant studies in animals. It is proposed that dissemination of rare cancer stem cells may lead to metastatic disease and that resistance of such cells to multiple drugs and androgen ablation make them responsible for failure of current treatments. Thus further understanding of the cancer stem cell biology is needed for development of efficient rationally designed therapy permitting better targeting and better treatment outcomes for patients with prostate neoplasms.     

Mechanisms and functional implications of adult neurogenesis

The generation of new neurons is sustained throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. In this review, we discuss the factors that regulate proliferation and fate determination of adult neural stem cells and describe recent studies concerning the integration of newborn neurons into the existing neural circuitry. We further address the potential significance of adult neurogenesis in memory, depression, and neurodegenerative disorders such as Alzheimer's and Parkinson's 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.     

Stem cell‐based therapy for Huntington's disease

Huntington's disease (HD) is a late‐onset neurodegenerative disease characterized by a progressive loss of medium spiny neurons in the basal ganglia. The development of stem cell‐based therapies for HD aims to replace lost neurons and/or to prevent cell death. This review will discuss pre‐clinical studies which have utilized stem or progenitor cells for transplantation therapy using HD animal models. In several studies, neural stem and progenitor cells used as allotransplants and xenografts have been shown to be capable of surviving transplantation and differentiating into mature GABAergic neurons, resulting in behavioral improvements. Beneficial effects have also been reported for transplantation of stem cells derived from non‐neural tissue, for example, mesenchymal‐ and adipose‐derived stem cells, which have mainly been attributed to their secretion of growth and neurotrophic factors. Finally, we review studies using stem cells genetically engineered to over‐express defined neurotrophic factors. While these studies prove the potential of stem cells for transplantation therapy in HD, it also becomes clear that technical and ethical issues regarding the availability of stem cells must be solved before human trials can be conducted. J. Cell. Biochem. 114: 754–763, 2013. © 2012 Wiley Periodicals, Inc.     

Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs

Deriving lung progenitors from patient-specific pluripotent cells is a key step in producing differentiated lung epithelium for disease modeling and transplantation. By mimicking the signaling events that occur during mouse lung development, we generated murine lung progenitors in a series of discrete steps. Definitive endoderm derived from mouse embryonic stem cells (ESCs) was converted into foregut endoderm, then into replicating Nkx2.1+ lung endoderm, and finally into multipotent embryonic lung progenitor and airway progenitor cells. We demonstrated that precisely-timed BMP, FGF, and WNT signaling are required for NKX2.1 induction. Mouse ESC-derived Nkx2.1+ progenitor cells formed respiratory epithelium (tracheospheres) when transplanted subcutaneously into mice. We then adapted this strategy to produce disease-specific lung progenitor cells from human Cystic Fibrosis induced pluripotent stem cells (iPSCs), creating a platform for dissecting human lung disease. These disease-specific human lung progenitors formed respiratory epithelium when subcutaneously engrafted into immunodeficient mice.     

Human umbilical cord blood cells: a new alternative for myocardial repair?

Cell therapy for myocardial disease is a rapidly progressive field. However, present strategies of cell transplantation into the infarcted myocardium have limitations from practical points of view. One of the biggest challenges is to achieve a sufficient number of suitable cells. Umbilical cord blood (UCB), an unlimited source of stem/progenitor cells that could be used for transplantation into the injured heart, is readily available. The aim of our review is to describe the potential and prospect of UCB as a new supplier of cells for myocardial repair. The use of UCB stem cells might be of importance to elderly and sick people in whom the availability of autologous stem cells is limited.     

神经干细胞巢成分及调节机制的研究进展

神经干细胞（NSCs）是一类具有自我更新和多向分化潜能的细胞。在特定的条件下能够分化成神经元、星形胶质细胞和少突胶质细胞,从而参与神经发生和损伤修复。调节NSCs的特定微环境,通常称为神经干细胞巢,包括多个细胞群,其贡献目前正在积极探索。了解NSCs及其微环境成分之间的相互作用,对于开发治疗神经退行性疾病及脊髓损伤的疗法至关重要。本篇综述描述并讨论了最新的研究,确定了新的成分在神经干细胞巢中的作用。这些发现给这个领域带来了新的概念。本综述评估这些最新进展,提高对NSCs微环境及其对NSCs功能的影响的认识。     

Advance in metabolism and target therapy in breast cancer stem cells

Breast cancer, like many other cancers, is believed to be driven by a population of cells that display stem cell properties. Recent studies suggest that cancer stem cells (CSCs) are essential for tumor progression, and tumor relapse is thought to be caused by the presence of these cells. CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies. Additionally, the metabolic properties of cancer cells differ markedly from those of normal cells. The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells. Metabolic targeting of breast CSCs (BCSCs) may be a very effective strategy for anti-cancer treatment of breast cancer cells. Thus, in this review, we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.     

间充质干细胞在动脉粥样硬化治疗中的研究进展

动脉粥样硬化是一种病因复杂的血管壁慢性炎症性疾病。动脉粥样硬化及其相关并发症已成为人类死亡的主要原因,然而,其病因和发病机制尚未完全阐明,治疗效果还不满意。目前已经证实,动脉内皮细胞功能发生障碍是动脉粥样硬化的始动过程,内皮细胞功能失调和内皮细胞丢失是动脉粥样硬化症的主要特点;而血管平滑肌细胞的异常增生在动脉粥样硬化的发生发展中也扮演着重要角色。因此,探索有效措施促进有益的内皮细胞再生并抑制平滑肌细胞增生是血管损伤防治的关键。近年来有研究发现,体外输注的间充质干细胞能够向受损部位募集,并进一步分化为内皮细胞,修复损伤血管。然而,也有研究显示体外输注的间充质干细胞还可以分化为血管平滑肌细胞进而在血管局部增生,参与血管再狭窄的发生。文中综述了间充质干细胞输注对动脉粥样硬化发展的最新研究进展,希望为后续开展的用间充质干细胞治疗动脉粥样硬化的研究提供一定的参考。     

Investigating monogenic and complex diseases with pluripotent stem cells

Human genetic studies have revealed the molecular basis of countless monogenic diseases but have been less successful in associating phenotype to genotype in complex multigenic conditions. Pluripotent stem cells (PSCs), which can differentiate into any cell type, offer promise for defining the functional effects of genetic variation. Here, we recount the advantages and practical limitations of coupling PSCs to genome-wide analyses to probe complex genetics and discuss the ability to investigate epigenetic contributions to disease states. We also describe new ways of using mice and mouse embryonic stem cells (ESCs) in tandem with human stem cells to further define genotype-phenotype relationships.     

Autophagy in stem cells

Autophagy is a highly conserved cellular process by which cytoplasmic components are sequestered in autophagosomes and delivered to lysosomes for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future.     

Adipose-derived stem cells and chondrogenesis

Cartilage has only a very limited capacity to renew its original structure. Stem cells have been used to repair damaged cartilage, and recent studies have indicated that stem cells from adipose tissue are attractive cell sources that have the capacity of multipotentiality to differentiate into osteogenic, chondrogenic, myogenic, neurogenic and endothelial cells. Adipose-derived stem cells (ASC) have unique characteristics compared with stem cells from BM. At present, ASC have been studied to promote chondrogenesis. This review discusses the application of ASC to cartilage formation.     

Lung Cancer Stem Cells and Implications for Future Therapeutics

Lung cancer is the most dreaded of all cancers because of the higher mortality rates associated with it worldwide. The various subtypes of lung cancer respond differently to a particular treatment regime, which makes the therapeutic interventions all the more complicated. The concept of cancer stem cells (CSCs) is based primarily on the clinical and experimental observations that indicate the existence of a subpopulation of cells with the capacity to self-renew and differentiate as well as show increased resistance to radiation and chemotherapy. They are considered as the factors responsible for the cases of tumor relapse. The CSCs may have significant role in the development of lung tumorigenesis based on the identification of the CSCs which respond during injury. The properties of multi-potency and self-renewal are shared in common by the lung CSCs with the normal pluripotent stem cells which can be isolated using the similar markers. This review deals with the origin and characteristics of the lung cancer stem cells. The role of different markers used to isolate lung CSCs like CD44, ALDH (aldehyde dehydrogenase), CD133 and ABCG2 (ATP binding cassette sub family G member 2) have been discussed in detail. Analysis of the developmental signaling pathways such as Wnt/β-catenin, Notch, hedgehog in the regulation and maintenance of the lung CSCs have been done. Finally, before targeting the lung CSC biomarkers for potential therapeutics, challenges faced in lung cancer stem cell research need to be taken into account. With the accepted notion that the CSCs are to blame for cancer relapse and drug resistance, targeting them can be an important aspect of lung cancer therapy in the future.