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43.7:

Forced Transdifferentiation

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Cell Biology
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JoVE Core Cell Biology
Forced Transdifferentiation

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Forced transdifferentiation is converting a differentiated cell type directly into another mature cell type without going through an intermediate pluripotent stem cell state.

Natural transdifferentiation occurs when a gene encoding a major transcription factor is activated in a mature cell.

Artificial transdifferentiation can happen by introducing lineage-specific transcription factors or by modifying cells’ chemical environments. 

For example, mouse heart fibroblasts can be transdifferentiated into cardiomyocytes, which are heart muscle cells, by using viral vectors to introduce genes encoding specific transcription factors.

Transdifferentiation can also be induced chemically. For example, dexamethasone converts rat pancreatic exocrine cells into hepatocytes, which are liver cells.

Dexamethasone activates the expression of the transcription factor C/EBP β in mature pancreatic cells. C/EBP β is the master switch for differentiation, and when its expression is turned on, it gradually transforms pancreatic cells into hepatocytes.

Ongoing research on the transdifferentiation of human fibroblasts into neurons or cardiomyocytes in vitro has shown potential for regenerative medicine.

43.7:

Forced Transdifferentiation

Transdifferentiation, also known as lineage reprogramming, was first discovered by Selman and Kafatos in 1974 in silkmoths. They observed that the moths’ cuticle-producing cells transformed into salt-producing cells. Many such cases of natural transdifferentiation occur in organisms. In humans, pancreatic alpha cells can become beta cells. In newts, the loss of the eye’s lens causes the pigmented epithelial cells to transdifferentiate into the lens cells.

Artificial transdifferentiation occurs when a transcription factor is forced to be expressed in a mature cell type. Therapeutically, turning on the transcription factor, MyoD converts human fibroblasts into muscle cells. Another transcription factor, C/EBP α, transforms mature lymphocytes into macrophages. In rats, the chemical dexamethasone turns on the expression of a transcription factor, C/EBP β, to convert pancreatic exocrine cells into liver cells. This transdifferentiation likely occurs since both pancreatic and liver cells originate from neighboring regions of the endoderm during development. The reverse of this differentiation, i.e., conversion of liver cells into pancreatic exocrine cells, is also experimentally possible. 

Transdifferentiation of cells does not go through an intermediate pluripotent stem cell state; therefore, it has some advantages over differentiating cells from induced pluripotent stem cells (iPSCs). Some epigenetic marks must be removed while transdifferentiating cells, while all the epigenetic marks are erased while reprogramming iPSCs. Mutations are less likely to occur when cells directly transform from one mature type to another.

Suggested Reading

  1. Graf, T. (2013). Cell replacement therapies: iPS technology or transdifferentiation. Euro Stem Cell. November.