is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. It often represents an adaptive response in which one cell type that is sensitive to a particular stress is replaced by another cell type that is better able to withstand the adverse environment.
The most common epithelial metaplasia is columnar to squamous (Fig. 1), as occurs in the respiratory tract in response to chronic irritation. In the habitual cigarette smoker, the normal ciliated columnar epithelial cells of the trachea and bronchi are often replaced by stratified squamous epithelial cells. Stones in the excretory ducts of the salivary glands, pancreas, or bile ducts, which are normally lined by secretory columnar epithelium, may also lead to squamous metaplasia by stratified squamous epithelium. A deficiency of vitamin A (retinoic acid) induces squamous metaplasia in the respiratory epithelium. In all these instances the more rugged stratified squamous epithelium is able to survive under circumstances in which the more fragile specialized columnar epithelium might have succumbed. However, the change to metaplastic squamous cells comes with a price. In the respiratory tract, for example, although the epithelial lining becomes tough, important mechanisms of protection against infection— mucus secretion and the ciliary action of the columnar epithelium—are lost. Thus, epithelial metaplasia is a double-edged sword and, in most circumstances, represents an undesirable change. Moreover, the influences that predispose to metaplasia, if persistent, can initiate malignant transformation in metaplastic epithelium. Thus, a common form of cancer in the respiratory tract is composed of squamous cells, which can arise in areas where the normal columnar epithelium has been replaced by squamous epithelium.
Fig1. Metaplasia of columnar to squamous epithelium. A, Schematic diagram. B, Metaplasia of columnar epithelium (left) to squamous epithelium (right) in a bronchus.
Metaplasia from squamous to columnar type may also occur, as in Barrett esophagus, in which the esophageal squamous epithelium is replaced by intestinal-like columnar cells under the influence of refluxed gastric acid. Cancers may arise in these areas; these are typically glandular (adenocarcinomas).
Connective tissue metaplasia is the formation of cartilage, bone, or adipose tissue (mesenchymal tissues) in tissues that normally do not contain these elements. For example, bone formation in muscle, designated myositis ossificans, occasionally occurs after intramuscular hemorrhage. This type of metaplasia is less clearly seen as an adaptive response, and may be a result of cell or tissue injury.
Mechanisms of Metaplasia
Metaplasia does not result from a change in the phenotype of an already differentiated cell type; instead it is the result of a reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue. In a metaplastic change, these precursor cells differentiate along a new pathway. The differentiation of stem cells to a particular lineage is brought about by signals generated by cytokines, growth factors, and extracellular matrix components in the cells’ environment. These external stimuli promote the expression of genes that drive cells toward a specific differentiation pathway. A direct link between transcription factor dysregulation and metaplasia is seen with vitamin A (retinoic acid) deficiency or excess, both of which may cause metaplasia. Retinoic acid regulates gene transcription directly through nuclear retinoid receptors (Chapter 9), which can influence the differentiation of progenitors derived from tissue stem cells. How other external stresses cause metaplasia is unknown, but it is clear that they too somehow alter the activity of transcription factors that regulate differentiation.
