Nutrient-Induced Intestinal Cellular Reprogramming Unveiled in Fruit Flies

In this study, researchers have unveiled a fascinating phenomenon in mature adult organs, shedding light on a novel mechanism of adaptive growth. Their investigation, centered on fruit flies (Drosophila), has provided valuable insights into the process of dedifferentiation, where specialized cells with specific functions transform into less specialized, undifferentiated cells, akin to stem cells. These findings, published in the journal Developmental Cell, challenge the conventional association of dedifferentiation with severe injuries or stressful conditions typically observed during tissue regeneration and diseases like tumorigenesis.

What’s particularly intriguing is the discovery that enteroendocrine cells (EEs) within the intestinal epithelium undergo dedifferentiation into intestinal stem cells (ISCs) in response to nutritional changes, such as recovery from starvation. Hiroki Nagai, the first author of the study and a postdoc at Tohoku University’s Frontier Research Institute for Interdisciplinary Sciences (FRIS), explains that through meticulous experimentation, they identified a subset of enteroendocrine cells in the adult midgut of Drosophila that exhibit dedifferentiation into ISCs when nutrient levels fluctuate. Using in vivo lineage tracing of EEs and single-cell RNA sequencing, they pinpointed the dedifferentiating EE subpopulation and developed a genetic system for selectively removing ISCs derived from dedifferentiation, a process known as ablation.

Remarkably, their ablation experiments revealed that dedifferentiation plays a vital role in ISC expansion and subsequent intestinal growth following food intake. This finding contrasts with previous studies involving mice, which relied on massive stem cell ablation to induce dedifferentiation. In this research, stem cells were not lost but, rather, increased in response to nutritional stimuli. This critical distinction suggests that dedifferentiation is not limited to regenerative contexts but significantly contributes to organ remodeling during environmental adaptations.

Furthermore, the team uncovered the molecular mechanism driving nutrient-dependent dedifferentiation: a deficiency in dietary glucose and amino acids activates the JAK-STAT signaling pathway in EEs, facilitating the conversion of EEs into ISCs during post-starvation recovery. When combined with findings from other studies, this implies that nutrient-dependent dedifferentiation could be an evolutionarily conserved mechanism across species.

Yuichiro Nakajima, the corresponding author of the paper, suggests that this discovery could pave the way for controlling artificial cellular reprogramming in vivo. “If we figure out specific nutrients and the detailed signaling that induce dedifferentiation, we could control cell fate plasticity through nutritional intervention and/or pharmacological treatments.”

Looking ahead, the researchers plan to expand their focus to examine cell fate plasticity under various physiological conditions beyond nutrition, including reproduction, temperature, light, and exercise. Such investigations may uncover novel mechanisms underlying environmental adaptations.

For more information, you can refer to the original research article: Hiroki Nagai et al, “Nutrient-driven dedifferentiation of enteroendocrine cells promotes adaptive intestinal growth in Drosophila,” published in Developmental Cell (2023). DOI: 10.1016/j.devcel.2023.08.022.

Source: Tohoku University

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