ScienceWeek

CELL BIOLOGY: CELL PLASTICITY IN DIFFERENTIATION

The following points are made by N.D. Theise and I. Wilmut (Nature 2003 425:21):

1) Until recently it was generally thought that cells move forward along their respective differentiation paths, but never backward, and certainly without jumping from one path to another. This dogma of unidirectional, hierarchical cell lineages in tissue development, maintenance, and repair has been explained by the action of irreversible gene restrictions: as cells differentiate in a lineage, genes that might be required for other pathways are apparently irreversibly repressed.

2) However, exceptions to the loss of plasticity associated with such lineage restrictions have long been recognized in disease and repair. For example, the epithelium that lines the lungs of smokers is often seen to change from simple columnar cells to a stratifed configuration (a process called squamous metaplasia), and bone can be formed in injured skeletal muscle (osseous metaplasia). Experimentally, heterokaryons, which are created by transferring a nucleus from a cell of one type into a cell of a different type, show changes in nuclear gene expression that reflect the character of the host cell, demonstrating that differentiation is an actively maintained, dynamic state rather than a one-way street.

3) With the blossoming of stem-cell research, demonstrations of heretofore implausible genomic plasticity are now published almost weekly. Many reports describe the derivation of cells of several tissues from a single source population. Although the mechanisms of genomic plasticity remain poorly understood, the presence of plasticity suggests that gene-restriction mechanisms are not irreversible after all.

4) Four plasticity pathways have been documented in vivo and experimentally. These pathways may involve undifferentiated cells, situated within specialized tissues, that can switch developmental programs in response to injury. In the liver, for example, the tiniest cells lining the bile duct are "bipotent" --they can regenerate either hepatocytes or other, larger bile-duct-lining cells in the face of injury. If tissues contain truly totipotent cells, these cells might be "embryonic rests" persisting in adult tissues long after embryonic development is completed. Another possibility is that differentiated cell types may "de-differentiate" to an earlier, progenitor phenotype. This process is probably more common in neoplasia, particularly malignancy. Alternatively, differentiative leaps can be induced by experimental manipulation or, in vivo, in response to injury. Thus, cells of differentiated phenotypes can have wide developmental ranges, and are not confined to the tissues from which they are derived. In such "transdifferentiation" events, the influence of microenvironment, perhaps through changes in response to injury, would be key. Finally, fusion between cells in some injury models can lead to reprogramming of nuclei, similar to that seen in in vitro heterokaryon experiments.(1-4)

References:

1. Blau, H. M. Nature 419, 437 (2002).

2. Wilmut, I. et al. Nature 419, 583–586 (2002).

3. Theise, N. D. & Krause, D. S. Leukemia 16, 542–548 (2002).

4. Cavaleri, F. & Scholer, H. R. Cell 113, 551–552 (2003).

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