Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is characterized by the accumulation of fibroblasts/myofibroblasts and aberrant remodeling of the lung parenchyma. However, the sources of fibroblasts in IPF lungs are unclear. Fibrocytes are circulating progenitors of fibroblasts implicated in wound healing and fibrosis. In this study we evaluated evidence for the presence of fibrocytes in the lung of patients with idiopathic pulmonary fibrosis by immunofluorescence and confocal microscopy. Fibrocytes were identified in tissues in 8 out of 9 fibrotic lungs. Combinations including CXCR4 and a mesenchymal marker stained significantly more fibrocytes/mm(2) of tissue compared with combinations using CD34 or CD45RO with mesenchymal markers: CXCR4/procollagen-I (10.3+/-2.9fibrocytes/mm(2)) and CXCR4/prolyl-4-hydroxylase (4.1+/-3.1), versus CD34/procollagen-I (2.8+/-3.0), CD34/alphaSMA (2.2+/-1.6) and CD45RO/prolyl-4-hydroxylase (1.3+/-1.6); p<0.003. There was a positive correlation between the abundance of fibroblastic foci and the amount of lung fibrocytes (r=0.79; p<0.02). No fibrocytes were identified in normal lungs. The fibrocyte attractant chemokine CXCL12 increased in plasma [median: 2707.5pg/ml (648.1-4884.7) versus 1751.5pg/ml (192.9-2686.0) from healthy controls; p<0.003)] and was detectable in the bronchoalveolar lavage fluid of 40% of the patients but not in controls. In the lung CXCL12 was strongly expressed by alveolar epithelial cells. A negative correlation between plasma levels of CXCL12 with lung diffusing capacity for carbon monoxide (DLCO) (r=-0.56; p<0.03) and oxygen saturation on exercise was found (r=-0.41; p<0.04). These findings indicate that circulating fibrocytes, likely recruited through the CXCR4/CXCL12 axis, may contribute to the expansion of the fibroblast/myofibroblast population in idiopathic pulmonary fibrosis.     

Cell division and tissue repair following localized damage to the mammalian lung.

Small local wounds on the surface of the mouse lung, produced by cauterization, healed by a typical reparative process involving cell migration and increased cell division in alveolar and bronchial tissues. The local cell division response closely resembled the compensatory cell division response in the same organ which follows unilateral pneumonectomy or unilateral collapse of the lung: initially there was an increase in the rate of DNA synthesis followed by an increased rate of entry into mitosis, both of these functions returning to normal levels within a few days. It is therefore suggested that both types of response are governed by a single regulatory mechanism. The results do not support the view that the rate of cell division is regulated by systemically-circulating mitotic control factors and it is proposed that changes in the cell division rate, both in the reparative and in the compensatory types of response, are determined by local alterations in the concentration of regulatory metabolites. The magnitude of the cell division response was much greater in bronchial than in alveolar tissue, a result which is consistent with the view that new alveolar tissue may be produced by the proliferation and diffentiation of bronchial cells.     

Fibrocytes can be reprogrammed to promote tissue remodeling capacity of dermal fibroblasts

Fibroblasts play a pivotal role in wound healing process participating in both tissue fibrosis and remodeling. However, it remains unclear which factors activate such diversity of fibroblast responses and how this decision-making process is made. Previous reports have demonstrated that wound milieu stimulates the transformation of circulating precursor cells into fibrocytes. These pro-fibrogenic cells promote the collagen production by resident fibroblasts. Conversely, recruited cells with anti-fibrogenic profile that can compete with fibrocytes have not been identified. This report describes a novel transdifferentiation process of fibrocytes induced by changing culture conditions. The reprogrammed fibrocytes markedly increased cell proliferation and MMP-1 expression in dermal fibroblasts. The MMP-1 up-regulation was directly related to the number of fibrocytes that followed this cell transformation. In vitro and in vivo results have confirmed that TGF-β deprivation plays an important role in this novel fibrocyte differentiation pathway. Our findings demonstrate that, changing the fibrocyte commitment, it is possible to exponentially stimulate the tissue remodeling capacity of dermal fibroblasts. These results will open new research approaches to understand the role of cell transdifferentiation and local environment not only in the wound healing process of skin, but also in several other fibrocyte-associated diseases such as lung fibrosis, asthma, liver cirrhosis, chronic pancreatitis, and atherosclerosis.     

循环纤维细胞及其在肺纤维化中的作用

循环纤维细胞(crculating fibrocytes CF)是一类骨髓来源的间质性细胞,可以同时表达造血细胞、单核细胞和成纤维细胞系的细胞标记。现有越来越多动物实验证据表明,CF的分化、转移功能在慢性炎症反应和胶原过度沉积中起着重要作用。近年来的实验表明,对CF的计数可以作为纤维化类疾病发展过程中的生物标记物,尤其在肺纤维化中更加明显。特发性肺纤维化是一种慢性肺部功能失调疾病,确诊后病人5年生存率低于30%。特发性肺纤维化是一种慢性肺部功能失调疾病,确诊后病人5年生存率低于30%。传统的免疫学疗法疗效很差。最近人们开始把注意力集中到对始祖干细胞的免疫调节机制上来。随着对循环纤维细胞研究的不断深入,对特发性纤维化的发病原因以及治疗研究方面有了较大发展。     

循环纤维细胞及其在肺纤维化中的作用

循环纤维细胞（circulating fibrocytes CF）是一类骨髓来源的间质性细胞,可以同时表达造血细胞、单核细胞和成纤维细胞系的细胞标记。现有越来越多动物实验证据表明,CF的分化、转移功能在慢性炎症反应和胶原过度沉积中起着重要作用。近年来的实验表明,对CF的计数可以作为纤维化类疾病发展过程中的生物标记物,尤其在肺纤维化中更加明显。特发性肺纤维化是一种慢性肺部功能失调疾病,确诊后病人5年生存率低于30％。特发性肺纤维化是一种慢性肺部功能失调疾病,确诊后病人5年生存率低于30％。传统的免疫学疗法疗效很差。最近人们开始把注意力集中到对始祖干细胞的免疫调节机制上来。随着对循环纤维细胞研究的不断深入,对特发性纤维化的发病原因以及治疗研究方面有了较大发展。     

Fibrocytes and activated fibrocytes in the healing of an open skin wound

The microscopic, electron microscopic and immunohistochemical observation of biopsy specimens taken at an early stage, at close and regular intervals (every 4 hours), from open skin wounds created in the pig and the monkey, together with quantitative analysis of the various cell types in the granulation tissue, supports the conception that the activated fibrocyte (fibroblast) originates from the fibrocyte of the wound edges and thus completes some earlier experimental studies. We describe here the various stages of the differentiation of the wound edge fibrocyte into an activated fibrocyte and its proliferation and migration from the edges to the site of the wound. This does not exclude the possibility that local mesenchymal cells take part in the formation of activated fibrocytes. The activated fibrocyte build the collagen of the granulation tissue and then remodel and ensure wound contraction by becoming fibroclasts and myofibroblasts. This article defines the signification of the terms fibrocyte, activated fibrocyte, fibroblast and activated fibroblast.     

Fibrocytes: emerging effector cells in chronic inflammation

Fibrocytes are mesenchymal cells that arise from monocyte precursors. They are present in injured organs and have both the inflammatory features of macrophages and the tissue remodelling properties of fibroblasts. Chronic inflammatory stimuli mediate the differentiation, trafficking and accumulation of these cells in fibrosing conditions associated with autoimmunity, cardiovascular disease and asthma. This Opinion article discusses the immunological mediators controlling fibrocyte differentiation and recruitment, describes the association of fibrocytes with chronic inflammatory diseases and compares the potential roles of fibrocytes in these disorders with those of macrophages and fibroblasts. It is hoped that this information prompts new opportunities for the study of these unique cells.     

Endogenous and exogenous stem cells: a role in lung repair and use in airway tissue engineering and transplantation

Rapid repair of the denuded alveolar surface after injury is a key to survival. The respiratory tract contains several sources of endogenous adult stem cells residing within the basal layer of the upper airways, within or near pulmonary neuroendocrine cell rests, at the bronchoalveolar junction, and within the alveolar epithelial surface, which contribute to the repair of the airway wall. Bone marrow-derived adult mesenchymal stem cells circulating in blood are also involved in tracheal regeneration. However, an organism is frequently incapable of repairing serious damage and defects of the respiratory tract resulting from acute trauma, lung cancers, and chronic pulmonary and airway diseases. Therefore, replacement of the tracheal tissue should be urgently considered. The shortage of donor trachea remains a major obstacle in tracheal transplantation. However, implementation of tissue engineering and stem cell therapy-based approaches helps to successfully solve this problem. To date, huge progress has been achieved in tracheal bioengineering. Several sources of stem cells have been used for transplantation and airway reconstitution in animal models with experimentally induced tracheal defects. Most tracheal tissue engineering approaches use biodegradable three-dimensional scaffolds, which are important for neotracheal formation by promoting cell attachment, cell redifferentiation, and production of the extracellular matrix. The advances in tracheal bioengineering recently resulted in successful transplantation of the world's first bioengineered trachea. Current trends in tracheal transplantation include the use of autologous cells, development of bioactive cell-free scaffolds capable of supporting activation and differentiation of host stem cells on the site of injury, with a future perspective of using human native sites as micro-niche for potentiation of the human body's site-specific response by sequential adding, boosting, permissive, and recruitment impulses.     

Localization and activity of iNOS in normal human lung tissue and lung cancer tissue

Inducible nitric oxide synthase (iNOS) is one of three enzymes generating nitric oxide (NO) from the amino acid L-arginine. iNOS-derived NO plays an important role in several physiological and pathophysiological conditions. NO is a free radical which produces many reactive intermediates that account for its bioactivity. In the human lung, the alveolar macrophage is an important producer of cytokines and this production may be modified by NO. Moreover, high concentrations of NO have been shown to increase nuclear factor kappaB (NF-kB) activation. Recent investigations of NO expression in tumor tissue indicated that, at least for certain tumors, NO may mediate one or more roles during the growth of human cancer. We have studied iNOS in two tissue groups: normal human lung tissue and human lung cancer tissue. We localized iNOS in these tissues by immunohistochemistry and tested the mRNA expression by RT-PCR, the protein level by Western blot, and the protein activity by radiometric analysis. The results demonstrate different expression, localization and activity of iNOS in normal versus tumor tissue. This is suggestive of a role for NO production from iNOS in human lung cancer because high concentrations of this short molecule may transform to highly reactive compounds such as peroxynitrite (ONOO-); moreover, through the upregulator NF-kB, they can induce a chronic inflammatory state representing an elevated risk for cell transformation to cancer.     

Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche

Neural stem cells are retained in the postnatal subventricular zone (SVZ), a specialized neurogenic niche with unique cytoarchitecture and cell-cell contacts. Although the SVZ stem cells continuously regenerate, how they and the niche respond to local changes is unclear. Here we generated nestin-creER(tm) transgenic mice with inducible Cre recombinase in the SVZ and removed Numb/Numblike, key regulators of embryonic neurogenesis from postnatal SVZ progenitors and ependymal cells. This resulted in severe damage to brain lateral ventricle integrity and identified roles for Numb/Numblike in regulating ependymal wall integrity and SVZ neuroblast survival. Surprisingly, the ventricular damage was eventually repaired: SVZ reconstitution and ventricular wall remodeling were mediated by progenitors that escaped Numb deletion. Our results show a self-repair mechanism in the mammalian brain and may have implications for both niche plasticity in other areas of stem cell biology and the therapeutic use of neural stem cells in neurodegenerative diseases.     

Gap junctional communication in tissue inflammation and repair

Local injury induces a complex orchestrated response to stimulate healing of injured tissues, cellular regeneration and phagocytosis. Practically, inflammation is defined as a defense process whereby fluid and white blood cells accumulate at a site of injury. The balance of cytokines, chemokines, and growth factors is likely to play a key role in regulating important cell functions such as migration, proliferation, and matrix synthesis during the process of inflammation. Hence, the initiation, maintenance, and resolution of innate responses depend upon cellular communication. A process similar to tissue repair and subsequent scarring is found in a variety of fibrotic diseases. This may occur in a single organ such as liver, kidneys, pancreas, lung, skin, and heart, but fibrosis may also have a more generalized distribution such as in atherosclerosis. The purpose of this review is to summarize recent advances on the contribution of gap junction-mediated intercellular communication in the modulation of the inflammatory response and tissue repair.     

Protein-based tissue engineering in bone and cartilage repair

Bioactive proteins signal host or transplanted cells to form the desired tissue type. Matrix systems are utilized to locally deliver the proteins and to maintain effective protein concentrations. For some indications, a matrix is required to define the physical form of the regenerated tissue. Substantial progress has been made in bone tissue engineering in recent years, based on the results of controlled clinical studies using bone morphogenetic proteins. Ongoing research in this area centers on the design of additional delivery matrices to expand the clinical indications, using synthetic delivery systems that mimic biological qualities of the natural materials currently in use. Although a similar rationale exists for the regeneration of articular cartilage with bioactive factors, advancement in this area has not been as substantial.     

Protein- and gene-based tissue engineering in bone repair

A tissue engineering approach to bone regeneration includes the use of a scaffold, cells and bioactive factors alone or in various combinations. Several investigators have demonstrated enhanced bone formation when the tissue-engineered construct possesses traits inherent to autogenic bone grafts, namely osteoconductivity, osteoinductivity and osteogenicity. Use of the biodegradable polymer poly(lactide-co-glycolide) in combination with bone morphogenetic protein or primary cells genetically modified to release osteogenic protein have demonstrated the ability to induce osteogenic differentiation of, and subsequent mineralization by, muscle-derived cells and mesenchymal stem cells in both in vitro and in vivo applications.     

Gap junctional communication in tissue inflammation and repair

Local injury induces a complex orchestrated response to stimulate healing of injured tissues, cellular regeneration and phagocytosis. Practically, inflammation is defined as a defense process whereby fluid and white blood cells accumulate at a site of injury. The balance of cytokines, chemokines, and growth factors is likely to play a key role in regulating important cell functions such as migration, proliferation, and matrix synthesis during the process of inflammation. Hence, the initiation, maintenance, and resolution of innate responses depend upon cellular communication. A process similar to tissue repair and subsequent scarring is found in a variety of fibrotic diseases. This may occur in a single organ such as liver, kidneys, pancreas, lung, skin, and heart, but fibrosis may also have a more generalized distribution such as in atherosclerosis. The purpose of this review is to summarize recent advances on the contribution of gap junction-mediated intercellular communication in the modulation of the inflammatory response and tissue repair.     

Langerhans cells are essential components of the angiogenic niche during murine skin repair

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