transdifferentiation

transdifferentiation, conversion of one differentiated (mature) cell type into another cell type. Transdifferentiation occurs naturally in only a few instances of regeneration. A celebrated example is the Wolffian regeneration of the lens in newts, where removal of the lens of the eye provokes the formation of a new lens derived from the cells of the iris.

Transdifferentiation is a subset of a more general set of cell-type interconversion called metaplasia, in which the starting cell type can be either differentiated or undifferentiated. In the latter instance, a stem cell or progenitor cell for a particular tissue type becomes transformed into a progenitor cell for a different tissue type. Metaplasias are well known in human pathology. For example, intestinal metaplasia of the stomach involves the formation of patches of intestinal epithelium within the gastric epithelium that normally lines the stomach. The mechanism of metaplasia is thought to involve the activation or repression of specific transcription factors that control tissue-type identity. In some cases, transcription-factor switches have been associated with the occurrence of specific metaplasias. For example, in mice, the transcription factor Cdx2, which is normally required for the development of the intestine, can drive the occurrence of intestinal metaplasia if it is incorrectly expressed in the stomach.

Transdifferentiation is of particular interest in the field of regenerative medicine, since transdifferentiated cells already exist in a mature state, avoiding concerns about the fate of the cells following transplantation into the patient. (By contrast, the fate of stem cells, which exist in an undifferentiated state, is more difficult to control.) However, experimental success with transdifferentiation using human cells has been limited. To prove the occurrence of transdifferentiation, it is necessary to precisely define the phenotype (observable characteristics) of the starting and the final cell type. It is also necessary to provide evidence of a cell-lineage relationship (a shared developmental history) to exclude artifacts such as selective overgrowth of one cell population by another. Evidence of cell-lineage relationships has not always been apparent, however, leading to some controversy about whether transdifferentiation has occurred at all in experimental cell populations.

An example of successful transdifferentiation of human cells has been the generation of insulin-producing beta cells from human adipose-tissue-derived stromal cells. Functional insulin-producing cells also have been generated from adult human liver cells. Such insulin-producing cells could be used as cell-replacement therapy for diabetes mellitus, particularly type I diabetes, in which the destruction of the beta-cell-containing islets of Langerhans in the pancreas results in failed insulin production and a life-long inability to control blood glucose levels without the aid of insulin therapy.

Historically, reports suggested that donor bone marrow cells could enter host tissues such as the heart and central nervous system, where they then became functional cells of those tissues. Evidence for such transdifferentiation, however, is lacking. Indeed, it is thought unlikely that transdifferentiation is brought about simply by grafting or transplanting cells to a new position within an adult animal.