Plasticity and dedifferentiation within the pancreas: development, homeostasis, and disease

Abstract

Cellular identity is established by genetic, epigenetic, and environmental factors that regulate organogenesis and tissue homeostasis. Although some flexibility in fate potential is beneficial to overall organ health, dramatic changes in cellular identity can have disastrous consequences. Emerging data within the field of pancreas biology are revising current beliefs about how cellular identity is shaped by developmental and environmental cues under homeostasis and stress conditions. Here, we discuss the changes occurring in cellular states upon fate modulation and address how our understanding of the nature of this fluidity is shaping therapeutic approaches to pancreatic disorders such as diabetes and cancer.

Figure 1. The Transition between Different Cellular States in Response to Genetic Manipulation or Injury and the Connection to Pancreatic Disease

Schematic depicting the progressive cellular transitions that can potentially occur in response to insults and how these may contribute to the manifestation of different pancreatic disorders. A “Normal” cell can either change cellular identity to a novel fate, depicted as a “Transdifferentiated” cell, or lose functionality and become a “Dedifferentiated” cell. Reversal from a “Dedifferentiated” state has been observed in certain instances. Transition to a novel cellular phenotype (“Transdifferentiation”) could occur directly or through a dedifferentiated state. A hypothetical “Resting” state is also possible, wherein the cell ceases to function normally but retains key features of cellular identity and can presumably reverse back to a fully functional state. Prolonged stress, injury, or activation of oncogenic pathways can convert a “Dedifferentiated” cell into a diseased state, leading to pathogenesis. Such a state may also be achievable if the “Trans-differentiated” cell is unstable and amenable to further fate modulation. The reversibility of a diseased cell back to a “Normal” cell has great implications for therapy and remains to be established. Blue dashed arrows depict hypothetical fate changes. Detailed definitions of the different cellular states are noted.

Figure 2. Acinar Dedifferentiation Is Reminiscent of Embryonic Multipotent Progenitor Cells

(A) Schematic depicting how the different pancreatic lineages arise from a common multipotent progenitor cell that is most closely related to the acinar cell. (B) Schematic indicating points where cellular stress (resulting from injury, expression of pivotal transcription factors, metabolic pressure, or inflammation) leads to the dedifferentiation of mature acinar cells. ADM, acinar-to-ductal metaplasia.

Figure 3. Endocrine Fate Conversion within the Islet

Fate change between the different endocrine cells is observed under different conditions of stress. This may occur either directly or through a dedifferentiated state. Continued stress on the β cell can lead to dedifferentiation that causes diabetes.