# Dedifferentiation
**Dedifferentiation** is the process by which a partially or terminally differentiated cell reverts to a less differentiated stage within its own lineage, regaining the ability to proliferate and, in many cases, to redifferentiate and replace lost cells[1](https://www.nature.com/articles/s41536-020-00099-8). It is one of the main cellular mechanisms of tissue regeneration, alongside transdifferentiation (conversion of one differentiated cell type into another) and reprogramming (reversion to pluripotency)[2](https://doi.org/10.1038/nrm3043).
| Key fact | Detail |
|---|---|
| Definition | Reversal of a partially or terminally differentiated cell to a less differentiated stage within its own lineage, shown by changes in shape, gene expression, protein expression, and function[1](https://www.nature.com/articles/s41536-020-00099-8) |
| Role in regeneration | Enables cells without proliferative potential, such as mature cardiomyocytes and myelinating Schwann cells, to re-enter the cell cycle and redifferentiate[1](https://www.nature.com/articles/s41536-020-00099-8) |
| Classic model | Salamander limb regeneration proceeds by dedifferentiation and respecification; the dedifferentiated cell mass is the regeneration blastema[3](https://www.ncbi.nlm.nih.gov/books/NBK9971/) |
| Distinction from reprogramming | Dedifferentiation stays within the lineage; reprogramming restores pluripotency so cells can become almost any cell type[2](https://doi.org/10.1038/nrm3043) |
| Pathological side | Chondrocyte dedifferentiation in culture and disease shifts collagen type II to type I production and is associated with osteoarthritis[1](https://www.nature.com/articles/s41536-020-00099-8) |
| Species contrast | Zebrafish fully regenerate hearts after 20% ventricle removal; mammals, including humans, have very limited regenerative capacity, and dedifferentiation often does not occur after injury in mammals[1](https://www.nature.com/articles/s41536-020-00099-8) • [4](https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.14633) |
## Definition and scope
During normal differentiation, a less specialized cell becomes a more specialized type with stable morphology, structure, and function, while self-renewal ability and pluripotency decline[1](https://www.nature.com/articles/s41536-020-00099-8). Dedifferentiation runs this process in reverse within the same lineage. The phenomenon is manifested by a change in the cell's shape, gene expression pattern, protein expression pattern, and function[1](https://www.nature.com/articles/s41536-020-00099-8).
The term has also been stretched. It originally referred to a loss of the terminally differentiated state in favor of a reacquired capacity to proliferate, but many contemporary biologists extend it to mean the loss of a stable phenotype and the reacquisition of cellular plasticity. The cell biologist Elizabeth Hay cautioned that this broader usage would lead to terminological chaos[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC10636051/).
**Relation to neighboring processes.** Dedifferentiation differs from transdifferentiation, in which one mature, specialized cell type changes into another without entering a pluripotent state[6](https://www.sciencedirect.com/science/article/pii/S0167488917301118), and from reprogramming, which induces differentiated cells to revert to pluripotency, from which they can differentiate into almost any cell type[2](https://doi.org/10.1038/nrm3043). The two routes can be linked: in the newt eye, iris pigment epithelial cells first dedifferentiate into unpigmented cells and then transdifferentiate into lens cells, a sequence described by Wolff in 1895[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC5154913/). During dedifferentiation and transdifferentiation, well-defined intermediate cell types have been identified, whereas reprogramming appears largely stochastic[2](https://doi.org/10.1038/nrm3043).
## Dedifferentiation in natural regeneration
**Salamander limbs.** When an adult salamander limb is amputated, the remaining cells reconstruct a complete limb with all its differentiated cells arranged in the proper order, rebuilding only the missing structures: a wrist amputation yields a new wrist, not a new elbow. Salamanders accomplish this by dedifferentiation and respecification, forming a dedifferentiated cell mass called the regeneration blastema[3](https://www.ncbi.nlm.nih.gov/books/NBK9971/). During this process, mature cells dedifferentiate through inactivation of the retinoblastoma (RB) protein and then enter the cell cycle[1](https://www.nature.com/articles/s41536-020-00099-8).
This mechanism is not universal even among salamanders. The axolotl does not show muscle dedifferentiation during limb regeneration; new muscle fibers instead derive from the activation of a resident Pax7-expressing stem cell population[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6679358/).
**Heart.** [Zebrafish](https://www.edgepedia.org/zebrafish) fully regenerate their hearts even after 20% of the ventricle is removed[1](https://www.nature.com/articles/s41536-020-00099-8). Mammalian cardiomyocytes stop multiplying soon after birth, which underlies the inability to replace heart muscle damaged by myocardial infarction. A transient regenerative potential exists in the neonatal murine heart, induced by cardiomyocyte dedifferentiation, and mouse studies suggest dedifferentiation may be an essential prerequisite for cardiomyocyte proliferation[1](https://www.nature.com/articles/s41536-020-00099-8).
**Nerve.** After nerve injury, mature myelinating Schwann cells dedifferentiate, regain an immature expression pattern, proliferate, and redifferentiate to drive repair. They downregulate myelin genes such as myelin protein zero and Krox20/Egr-2, re-express immature markers including p75 neurotrophin receptor, NCAM, and L1, clear myelin and axonal debris, and produce neurotrophic factors that support axon regeneration[1](https://www.nature.com/articles/s41536-020-00099-8).
## Molecular regulation
Signaling pathways play a central role. Activation of Wnt/β-catenin signaling induces dedifferentiation of epidermal cells, articular chondrocytes, or endothelial cells for regeneration, and specific biomolecules trigger dedifferentiation of vascular smooth muscle cells or chondrocytes through mitogen-activated protein kinase (MAPK) pathways[1](https://www.nature.com/articles/s41536-020-00099-8).
In the injured heart, the inflammatory cytokine oncostatin M (OSM), a member of the interleukin-6 family, triggers the Ras/MEK/Erk cascade to induce cardiomyocyte dedifferentiation via the OSM receptor β. A positive feedback loop comprising YAP, TEAD1, and OSM mediates murine cardiomyocyte dedifferentiation[1](https://www.nature.com/articles/s41536-020-00099-8).
In Schwann cells, Notch signaling accelerates dedifferentiation of mature cells, the transcription factor c-Jun acts as a negative regulator of myelination whose depletion delays demyelination and suppresses dedifferentiation, and increased cAMP levels maintain differentiation while its removal rapidly induces dedifferentiation and proliferation[1](https://www.nature.com/articles/s41536-020-00099-8).
## Pathological dedifferentiation
Dedifferentiation can harm as well as repair. Chondrocytes cultured repeatedly in monolayers change from spherical cells to spindle-shaped fibroblast-like cells and shift from type II collagen (Col II) to type I collagen (Col I) expression, switching the tissue from hyaline cartilage to fibrous cartilage with considerably altered function[1](https://www.nature.com/articles/s41536-020-00099-8). Chondrocyte dedifferentiation shares features with osteoarthritis, including decreased aggrecan and Col II expression, and ultimately contributes to the disease[1](https://www.nature.com/articles/s41536-020-00099-8).
The consequences are tissue-specific. Dedifferentiated cardiomyocytes after injury are preferentially protected from apoptosis and re-enter the cell cycle for repair, while dedifferentiated chondrocytes gradually lose proliferative ability, undergo hypertrophy, and eventually die[1](https://www.nature.com/articles/s41536-020-00099-8). Whether dedifferentiation should be induced or suppressed, and to what extent, therefore depends on the tissue[1](https://www.nature.com/articles/s41536-020-00099-8).
## Therapeutic outlook
Because mammals have very limited regenerative capacity compared with most cold-blooded vertebrates, and dedifferentiation often does not occur after injury in mammals, researchers study amphibian and fish mechanisms to design regenerative strategies for humans[1](https://www.nature.com/articles/s41536-020-00099-8) • [4](https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.14633). Murine myotubes can dedifferentiate to a certain extent when stimulated by an extract from newt regenerating limbs, suggesting extrinsic signals can drive the process[1](https://www.nature.com/articles/s41536-020-00099-8).
A proposed clinical route is to obtain terminally differentiated cells noninvasively, induce dedifferentiation toward a stem-like state, propagate the cells in vitro, differentiate them into the desired cell type, and transplant them to regenerate damaged organs[1](https://www.nature.com/articles/s41536-020-00099-8). Dedifferentiation and transdifferentiation have been successfully achieved in vivo, and reprogramming additionally enables genetic manipulation such as correcting disease-inducing mutations[2](https://doi.org/10.1038/nrm3043). Innovative biomaterials are also being designed to regulate dedifferentiation[1](https://www.nature.com/articles/s41536-020-00099-8).
## References
1. [Yao, Y. & Wang, C. (2020). Dedifferentiation: inspiration for devising engineering strategies for regenerative medicine. npj Regenerative Medicine 5, 14.](https://www.nature.com/articles/s41536-020-00099-8)
2. [Jopling, C., Boue, S. & Izpisua Belmonte, J. C. (2011). Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nature Reviews Molecular Cell Biology 12, 79–89.](https://doi.org/10.1038/nrm3043)
3. [Regeneration. Developmental Biology, NCBI Bookshelf.](https://www.ncbi.nlm.nih.gov/books/NBK9971/)
4. [Pesaresi, M. et al. (2019). Dedifferentiation, transdifferentiation and cell fusion: in vivo reprogramming strategies for regenerative medicine. The FEBS Journal 286, 1074–1093.](https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.14633)
5. [Enduring questions in regenerative biology and the search for answers. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC10636051/)
6. [Transdifferentiation and reprogramming: Overview of the processes, their similarities and differences. Biochimica et Biophysica Acta.](https://www.sciencedirect.com/science/article/pii/S0167488917301118)
7. [Cellular plasticity: 1712 to the present day. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC5154913/)
8. [Model systems for regeneration: salamanders. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC6679358/)
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*Topic: Encyclopedia › Life and health › Biological foundations › Development and comparative physiology › Cellular, regenerative, and comparative physiology › Regeneration (biological) › Regeneration mechanisms*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license