Breaking down metaplasia

The definition of metaplasia is quite generic - the replacement of one cell type with another.  This implies nothing as to what biological process occurs and our understanding of the mechanisms that convert one cell type to another is immature at best.

There are at least three separate processes that can lead to metaplasia; 

1. Destruction of a cell population which is subsequently replaced by a separate proliferating/migrating cell population, 
2. Respecification of a stem cell or progenitor such that its progeny differentiate into the metaplastic cell types.
3. Direct conversion of a differentiated cell into another without an intermediary, 

The first of these processes, where a proliferating/migrating population fills in for cells that have been destroyed, may be typified by necrotizing sialometaplasia in the minor salivary glands of the oral cavity.  In this pathology the salivary glands undergo necrosis due to injury (i.e. infarction) and the overlying squamous epithelium proliferates down to replace the necrotic glands, filling in where ducts and acini once were. This is shown below.

Diane L. Carlson (2009) Necrotizing Sialometaplasia: A Practical Approach to the Diagnosis. Archives of Pathology & Laboratory Medicine: Vol. 133, No. 5, pp. 692-698

An emerging principle of stem cell biology is that metaplasia may result from the transdetermination of tissue stem cell [1, 2, 3]. Transdetermination is a state transition - the switch from one phenotypic state to another. The state transition concept applies to the processes of differentiation, dedifferentiation, transdifferentiation, and transdetermination as shown below.  Metaplasia may result from various combinations of state transitions.

A stem cell hierarchy is shown in the large box and represents normal differentiation in development and homeostasis. Stem Cells (SC1 and SC2) produce progenitor cells (P 1-3) that then fully differentiate into mature cell types (M1-6). Each step in the normal differentiation pathway is considered a state transition. Transdifferentiation is the transition of one differentiated cell state to another and is proposed to be more likely between closely related cell types (M1 to M2 > M1 to M3). Dedifferentiation is the transition from a more differentiated state to a less differentiated one (M1 to P1). Transdetermination is the transition from one undifferentiated state (SC1 or P2) to a more differentiated state that is not found in the normal developmental or homeostatic differentiation pathway. Transdetermination events are consistent with metaplasia.

Some types of metaplasia may indeed be due to transdetermination. Intestinal metaplasia of the esophagus is thought to arise by this route.  It is believed that a stem cell or progenitor resides in the ducts of the esophageal submucosal glands and facilitates the regeneration of the esophageal epithelium following reflux injury. The contents of the reflux are suspected to cause the transdetermination into the intestinal lineages.

Transdifferentiation, the direct conversion of a differentiated cell type into another, can be achieved experimentally by inducing expression of transcriptional regulators or growth factors.  Reprogramming pancreatic acinar cells by the expression of developmentally regulated genes such as Pdx-1, Ngn3, and Mafa has demonstrated that these mature cell types can be transdifferentiated into beta cells.  This is one of many experimental scenarios where developmentally related cell types can be interconverted. Reprogramming somatic cells is a hot topic in the regenerative medicine field and will be a feature of upcoming posts.

Are there other mechanisms of metaplasia? Post your ideas!

References
1. Eberhard, D. and D. Tosh, Transdifferentiation and metaplasia as a paradigm for understanding development and disease. Cell Mol Life Sci, 2008. 65(1): p. 33-40.
2. Tosh, D. and J.M. Slack, How cells change their phenotype. Nat Rev Mol Cell Biol, 2002. 3(3): p. 187-94.
3. Zhou, Q. and D.A. Melton, Extreme makeover: converting one cell into another. Cell Stem Cell, 2008. 3(4):