Transdifferentiation

Transdifferentiation, also known as lineage reprogramming, is a process in which one mature somatic cell transforms into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type. It is a type of metaplasia, which includes all cell fate switches, including the interconversion of stem cells. Current uses of transdifferentiation include disease modeling and drug discovery and in the future may include gene therapy and regenerative medicine. The term 'transdifferentiation' was originally coined by Selman and Kafatos in 1974 to describe a change in cell properties as cuticle producing cells became salt-secreting cells in silk moths undergoing metamorphosis. Transdifferentiation, also known as lineage reprogramming, is a process in which one mature somatic cell transforms into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type. It is a type of metaplasia, which includes all cell fate switches, including the interconversion of stem cells. Current uses of transdifferentiation include disease modeling and drug discovery and in the future may include gene therapy and regenerative medicine. The term 'transdifferentiation' was originally coined by Selman and Kafatos in 1974 to describe a change in cell properties as cuticle producing cells became salt-secreting cells in silk moths undergoing metamorphosis. Davis et al. 1987 reported the first instance of transdifferentiation where a cell changed from one adult cell type to another. Forcing mouse embryonic fibroblasts to express MyoD was found to be sufficient to turn those cells into myoblasts. There are no known instances where adult cells change directly from one lineage to another except Turritopsis dohrnii and in the Turritopsis Nutricula, a jellyfish that is theoretically immortal. Rather, cells dedifferentiate and then redifferentiate into the cell type of interest. In newts when the eye lens is removed, pigmented epithelial cells de-differentiate and then redifferentiate into the lens cells.In the pancreas, it has been demonstrated that alpha cells can spontaneously switch fate and transdifferentiate into beta cells in both healthy and diabetic human and mouse pancreatic islets.While it was previously believed that oesophageal cells were developed from the transdifferentiation of smooth muscle cells, that has been shown to be false. The first example of functional transdifferentiation has been provided by Ferber et al. by inducing a shift in the developmental fate of cells in the liver and converting them into 'pancreatic beta-cell-like' cells. The cells induced a wide, functional and long-lasting transdifferentiation process that reduced the effects of hyperglycemia in diabetic mice. Moreover, the trans-differentiated beta-like cells were found to be resistant to the autoimmune attack that characterizes type 1 diabetes. The second step was to undergo transdifferentiation in human specimens. By transducing liver cells with a single gene, Sapir et al. were able to induce human liver cells to transdifferentiate into human beta cells. This approach has been demonstrated in mice, rat, xenopus and human tissues (Al-Hasani et al., 2013). Schematic model of the hepatocyte-to-beta cell transdifferentiation process. Hepatocytes are obtained by liver biopsy from diabetic patient, cultured and expanded ex vivo, transduced with a PDX1 virus, transdifferentiated into functional insulin-producing beta cells, and transplanted back into the patient. In this approach, transcription factors from progenitor cells of the target cell type are transfected into a somatic cell to induce transdifferentiation. There exists two different means of determining which transcription factors to use: by starting with a large pool and narrowing down factors one by one or by starting with one or two and adding more. One theory to explain the exact specifics is that ectopic Transcriptional factors direct the cell to an earlier progenitor state and then redirects it towards a new cell type. Rearrangement of the chromatin structure via DNA methylation or histone modification may play a role as well. Here is a list of in vitro examples and in vivo examples. In vivo methods of transfecting specific mouse cells utilize the same kinds of vectors as in vitro experiments, except that the vector is injected into a specific organ. Zhou et al. (2008) injected Ngn3, Pdx1 and Mafa into the dorsal splenic lobe (pancreas) of mice to reprogram pancreatic exocrine cells into β-cells in order to ameliorate hyperglycaemia. Somatic cells are first transfected with pluripotent reprogramming factors temporarily (Oct4, Sox2, Nanog, etc.) before being transfected with the desired inhibitory or activating factors. Here is a list of examples in vitro.