Dedifferentiation (pronounced dē-ˌdi-fə-ˌren-chē-ˈā-shən) is a transient process by which cells become less specialized and return to an earlier cell state within the same lineage. This suggests an increase in cell potency, meaning that, following dedifferentiation, a cell may possess the ability to re-differentiate into more cell types than it did prior to dedifferentiation. This is in contrast to differentiation, where differences in gene expression, morphology, or physiology arise in a cell, making its function increasingly specialized.
The loss of specialization observed in dedifferentiation can be noted through changes in gene expression, physiology, function witin the organism, proliferative activity, or morphology. While it can be induced in a laboratory setting through processes like direct reprogramming and the production of induced pluripotent stem cells, endogenous dedifferentiation processes also exist as a component of wound healing mechanisms.
History
References to dedifferentiation can be found as far back as 1915, where Charles Manning Child described dedifferentiation as a “return or approach to the embryonic or undifferentiated condition”. While Manning's research was in reference to plants, it helped establish the foundation for our modern day understanding of dedifferentiation and cell plasticity. Just as plant cells respond to injury by undergoing callus formation via dedifferentiation, some animal models dedifferentiate their cells to form blastema, which are analogous to plant calluses, after limb amputation.
In the 1940s C. H. Waddington created the “Epigenetic Landscape”, a diagrammatic representation of cell fate from less differentiated to more differentiated cell types. Here, the concept of a marble moving downhill through various paths is used to represent cell decision-making and cell potency, thus visualizing how cells can take different paths of differentiation to reach a final state. Dedifferentiation would be represented by the marble moving uphill through the pathways it has already taken, until it settles somewhere above the most downhill location.
In our modern day understanding of dedifferentiation, some controversies remain when defining the boundaries of its definition. Some claim that dedifferentiation is strictly limited to the same cell lineage from which it is derived. However, others say that it can be used to describe a general increase in cell potency.
Mechanisms
The mechanism by which dedifferentiation occurs has not been completely illuminated. The pathways discussed below are found to be closely related to dedifferentiation and regeneration in some species. Because not one pathway has been elucidated as necessary for all dedifferentiation and regeneration, it is possible that the mechanism functions differently in different species.
Observed markers of dedifferentiation
For dedifferentiation, genes that are in the extracellular matrix play an important role. For example, MMP, the matrix metalloproteinase, has shown up-regulated activity during early stages of limb regeneration. Matrix Metalloproteinases are responsible for degradation of both non-matrix and matrix proteins. MMP degrades proteins in the extracellular matrix of a cell, resulting in the destabilization of the differentiated cell identity.
However, the markers selected to represent dedifferentiation can differ according to tissue and cell types that are being studied. For example, in mice myotubes, dedifferentiation is marked by a decreased expression of Myogenin, a protein present in differentiated myotubes.
Involved Pathways
Some of the pathways that have shown interaction in dedifferentiation are MSX1, Notch 1, BMP, and Wnt/β-Catenin.
MSx1 , a gene that is a member of the homeobox family, encodes a transcriptional repressor that can prevent differentiation in epithelial and mesenchymal progenitor cell types. This repressor would be able to keep cells undifferentiated during development. Reduced levels of Msx1 expression resulted in inability to regenerate tadpole tails.
Bone Morphogenic Proteins (BMP ) are a group of signaling molecules involved in growth and development in many systems, including bone, embryogenesis , and homeostasis . The BMP pathway has been shown to be necessary for dedifferentiation and regeneration in tadpoles. Downregulation of the BMP pathway led to a downregulation of MSx1, resulting in no regeneration in the tadpole. Once BMP expression was restored, Msx1 expression was also restored, and regeneration proceeded.19 Similar studies have shown similar results in mouse digit tip regeneration.
