Fibrocytes in chronic lung disease – Facts and controversies

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Abstract

Fibrocytes are bone marrow-derived mesenchymal cell precursors, defined primarily by their ability to co-express markers of both haematopoietic (e.g. CD45 or CXCR4) and stromal (e.g. collagen) lineages. Fibrocytes in culture also have ultrastructural cell surface features that distinguish them from other leukocytes. Extensive efforts have helped to characterise fibrocytes phenotypically and functionally, but it is still unclear exactly how these cells contribute to tissue repair and/or pathologic fibrosis. Nevertheless, the varied levels of fibrocytes in blood have raised considerable interest as a biomarker of disease activity, such as chronic lung diseases, including pulmonary fibrosis, asthma and pulmonary hypertension. These cells also may become a novel therapeutic target for these difficult to treat disorders. This review will briefly summarize the current knowledge about fibrocytes in human lung disease and in animal disease models and highlight areas of consensus as well as issues that remain controversial to date.

Introduction

Fibrocytes are circulating mesenchymal cell precursors, derived from bone marrow and first identified by Bucala et al. [1] in 1994, studying the biology of wound repair and determining which factors were contributing to the development and accumulation of fibroblasts. Since this initial discovery, additional studies have contributed to the characterization of fibrocytes, with respect to their morphology, growth characteristics in vitro, their biological roles in vivo, and their potential utility as a biomarker and/or treatment target in human disease.

Despite extensive efforts, the role and functions of this cell in tissue repair and pathobiology of chronic tissue remodelling are still unclear. In the current literature, there are discrepancies concerning the ability to culture fibrocytes, their detection in the peripheral blood and their mechanistic role in disease, most likely related to different methodologies and variable disease stages and animal models that are used to investigate the fibrocyte. In the last few years there have been a number of excellent reviews on the subject of fibrocytes highlighting the current knowledge about these cells. This review will focus on what has been consistently shown about fibrocytes in humans and some of the areas that still require further attention and scientific work.

Section snippets

Multiple markers are used to identify fibrocytes

Fibrocytes are circulating bone marrow-derived mesenchymal progenitor cells [2], [3], [4], [5] co-expressing haematopoietic stem cell markers, monocyte lineage markers and fibroblast products [6], [7]. Fibrocytes, like some dendritic cell subsets, are most likely derived from precursors of the monocyte lineage, supported by the observation that they express the major histocompatibility complex class I and class II and the co-stimulatory molecules CD80 and CD86 [1], [6], [8]. Current evidence

Fibrocytes demonstrate phenotype plasticity

At present there is no single specific marker for fibrocytes (see Fig. 1). This may be due to the apparent plasticity and constant change of these cells and may explain some of the difficulties in tracking them. It is, however, believed that human fibrocytes in circulation probably represent an obligate intermediate stage of differentiation of one of the precursors of the monocyte lineage into mature fibroblasts and myofibroblasts at the tissue sites [14]. While many studies support the notion

Fibrocyte isolation and culture

Whilst identification and quantification of fibrocytes in peripheral blood is relatively straight forward, depending on the marker panel that is used, the isolation and culturing of these cells remains difficult. There are several protocols published, and most groups seem to follow the original method developed by Bucala et al. [8], [27] using RPMI- or DMEM-based culture media, supplemented with 10–20% foetal bovine serum. Modifications to this protocol have been proposed by Pilling et al. [28]

Potential roles of fibrocytes in tissue repair

The putative roles for fibrocytes in tissue injury and repair vary between the organ systems and experimental models studied. They are found in different models of tissue repair and experimental fibrosis including wounded skin, asthma, pulmonary vascular remodelling, and lung and liver fibrosis [2], [16], [28], [29], [30], [31]. Fibrocytes can be detected in human fibrotic disorders including idiopathic pulmonary fibrosis (IPF), chronic asthma, nephrogenic fibrosing dermopathy, scleroderma and

Fibrocytes are present in a variety of chronic lung diseases

There is evidence suggesting that fibrocytes contribute to lung remodelling at some stage [48], [49]. The presence of fibrocytes has been reported in the circulation and tissue of a variety of lung disorders in humans, e.g. in IPF, chronic asthma, and scleroderma (see Table 1). While there is no publication of a “normal” number of fibrocytes in tissue, there is some understanding of the numbers that can be expected in the circulation. Using the marker combination CD45+/Col-1 positivity, Bucala

Summary and outlook

The study of fibrocytes is an exciting new topic in the area of injury, repair and fibrosis in many organs and tissues. The cells themselves seem to be as dynamic as the entire field of research. Sometimes the promise of a new discovery runs ahead of the actual facts and knowledge, which may be the case for fibrocytes. Some of the current “facts” are: (1) Fibrocytes are versatile and multipotent mesenchymal cell precursors found in the peripheral blood. (2) Cells that look like fibrocytes can

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