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Induced Direct Transdifferentiation Shows Promise
Induced direct transdifferentiation (iT) results in the conversion of one mature cell type to another mature cell type. The procedure can convert cell phenotype across germ layers or within a germ layer. This kind of transdifferentiation is “direct” since host cells do not have to be dedifferentiated to a pluripotent state (iPS) and then redifferentiated with growth factors to the destination cell type. Thus, induced transdifferentiation holds promise to produce therapeutic cells without the need to “deprogram” cells into in iPS cells. Bypassing the iPS generation process can reduce the number of cellular manipulations required to transform mature cells into other mature cells.
While still in the experimental stage, induced direct transdifferentiation shows promise. Initially, the transdifferentiation process was initiated by introducing plasmids or viral vectors that express tissue specific growth factors into cells. Zhao et al. directly reprogrammed fully differentiated exocrine cells to insulin-producing cells that closely resembled Beta-cells through a combination of 3 factors. Reprogramming exocrine cells to Beta-cells occurred relatively quickly with an efficiency of up to 20%. The first insulin producing cells were observed as early as day 3 post-transduction. In addition, fibroblasts have been directly transdifferentiated to functional blood progenitor cells, neurons, and cardiomyocytes by the process. These data suggest that the level of expression of key transcription factors mediates the process of transdifferentiation. More recently, Kim et al showed that RNA can be used to initiate the transformation of fibroblasts into cardiomyocytes. This RNA mediated process is a step forward since the use of RNA will likely result in less chromosomal damage to cells, less genomic instability, and less tumorigenic potential than methods that rely on DNA transformation or viral vectors. Despite the recent progress more work is needed to prove that transdifferentiated cells are useful for therapeutic applications. It remains to be shown that iT cells can maintain stable conversion. Likewise, in vivo assays are needed to prove the suitability of iT cells for transplantation. Nevertheless, iT cells represent potential new cell sources for regenerative medicine.