Targeting β-cell dedifferentiation and transdifferentiation: opportunities and challenges

The most distinctive pathological characteristics of diabetes mellitus induced by various stressors or immune-mediated injuries are reductions of pancreatic islet beta-cell populations and activity. Existing treatment strategies cannot slow disease progression; consequently, research to genetically engineer beta-cell mimetics through bi-directional plasticity is ongoing. The current consensus implicates beta-cell dedifferentiation as the primary etiology of reduced beta-cell mass and activity. This review aims to summarize the etiology and proposed mechanisms of beta-cell dedifferentiation and to explore the possibility that there might be a time interval from the onset of beta-cell dysfunction caused by dedifferentiation to the development of diabetes, which may offer a therapeutic window to reduce beta-cell injury and to stabilize functionality. In addition, to investigate beta-cell plasticity, we review strategies for beta-cell regeneration utilizing genetic programming, small molecules, cytokines, and bioengineering to transdifferentiate other cell types into beta-cells; the development of biomimetic acellular constructs to generate fully functional beta-cell-mimetics. However, the maturation of regenerated beta-cells is currently limited. Further studies are needed to develop simple and efficient reprogramming methods for assembling perfectly functional beta-cells. Future investigations are necessary to transform diabetes into a potentially curable disease.