Home Medizin Forscher entdecken neuen Wirkmechanismus zwischen der Nährstoffanpassung von Darmstammzellen und dem Altern

Forscher entdecken neuen Wirkmechanismus zwischen der Nährstoffanpassung von Darmstammzellen und dem Altern

von NFI Redaktion

A recent study published in Science Advances used an organ-wide approach to quantitatively analyze cell number, size, and identity regulation in nutrient-induced tissue adaptation of the Drosophila midgut.

Study: mTOR stem cell signaling controls region-specific cell fate decisions during nutrient adaptation in the intestine.  Photo credit: Giovanni Cancemi/Shutterstock.com
Study: mTOR stem cell signaling controls region-specific cell fate decisions during nutrient adaptation in the intestine. Photo credit: Giovanni Cancemi/Shutterstock.com

Background

The adult intestine is a regionalized organ that changes its size and composition depending on nutrient availability, controlling the proliferation and differentiation of intestinal stem cells (ISCs). Nutrient intake influences the physiology of adult animals by altering the cell composition of organs through somatic stem cell activation. The nutrition significantly affects the volume and form of the small intestine, allowing the adjustment of signaling, absorption, and metabolic functions to the physiological requirements of the animals. The Drosophila midgut exhibits four unique cell types, all distinguished from ISCs. The size of the midgut varies significantly depending on nutrition.

About the Study

In the present study, researchers investigated the influence of nutrient signaling on cell fate decisions in the adult intestine, specifically regulating the proliferation and differentiation of intestinal stem cells (ISC).

For the study, flies were maintained at 25°C on a medium containing different nutrients, using the Holidic diet as the experimental diet. They dissected the gut tissue, which was fixed, washed, blocked, and stained with antibodies. They performed gut dissection and fluorescence-activated cell sorting (FACS) dissociation, sorting Growth 1 (G1) and G2 cells into RNA isolation buffer in three replicate samples of 80 to 100 intestines each. They extracted and amplified RNA, created and sequenced libraries, and imaged immune-stained midguts with confocal microscopes.

The researchers used Linear Analysis of the Midgut (LAM) to assess the growth regulation of intestinal stem cells (ISCs) in flies. They determined the maximal nuclear cross-sectional area in the midgut of starved and fed flies, and used the ISC marker Delta-LacZ to investigate feeding-induced size regulation. They also examined the involvement of the mTORC1 signaling pathway, a recognized cell size regulator, by measuring the p4EBP levels in regions R1, R2, R4, and R5. They reduced mTORC1 activity through Raptor-RNAi knockdown and evaluated nuclear area in ISCs.

The researchers explored the function and control of mTORC1 activity in cells of the Transforming Growth Factor (TGF) using Delta-Gal4 to express the Fluorescence Ubiquitination-based Cell Cycle Indicator (FUCCI) reporter, allowing them to examine 4EBP phosphorylation at different growth stages. They also examined gene expression at various developmental stages, assuming that cell size is related to ISC differentiation.

The team also investigated the relationship between mTORC1 signaling activity of intestinal stem cells and Delta expression by assessing regional Delta-LacZ intensity in starved and fed flies. They also examined whether mTORC1 actively inhibits the differentiation of EE cells. They compared the guts of older flies fed ad libitum with a diet to those of flies that had to engage in lifelong intermittent fasting.

Results

In flies, regional modulation of cell size, number, and differentiation characterizes the adaptation of intestinal nutrition. The mammalian target of rapamycin complex 1 (mTORC1) stimulates the growth of intestinal stem cells (ISCs), increases Delta expression, and directs cell fate determination towards the absorbent enteroendocrine lineage. In older flies, ISC mTORC1 signaling is dysregulated and insensitive to foods, which can be reduced by lifelong intermittent fasting. Nutrient-induced signals regulate the development of enterocytes (EC) and ISC differentiation region-specifically.

The study revealed regional differences in the adaptive development of the midgut, with the transition from fasting to fed state increasing ISC proliferation and EC growth, allowing for dynamic adjustment of midgut size in adults. The current understanding of midgut growth control is based on local quantifications of specific sites without global organ-wide insights. Feeding leads to unique changes in ISC daughter cells, enteroendocrine (EE) cells, and neuroblasts (EBs), with the region-specific mTORC1 activation determining ISC growth. The geographic distribution of ISC growth aligns with EB accumulation during feeding.

The results showed that the activation of ISC mTORC1 is associated with asymmetric ISC-EB cell pairs which rapidly proliferate during differentiation into the EC fate. ISCs can also develop into tiny diploid EE cells controlled by Notch signals. Large ISCs correlate with EB differentiation. ISC mTORC1 signaling increases Delta expression, regionally and nutritionally dependently. Large ISCs with robust mTORC1 activity express large amounts of Delta, governing differentiation into the EB fate in a region-specific manner.

High mTORC1 signaling influences the fate of EE cells. Raptor knockdown in Notch-LOF clones eliminated Prospero− p4EBP+ clusters, rendering them homogenous for Prospero+ cells. Intermittent fasting protects against age-related decreases in intestinal nutrition adaptation, meaning that the physiological nutrition-dependent control of mTORC1 signaling is lost in old ISCs but retained in intermittently fasting flies.

Conclusion

Overall, the study’s findings show that mTORC1 signaling is crucial for the fate of intestinal stem cells (ISCs) in response to nutrition. It reveals regionally different patterns of enterocyte development, cell number, and cell type distribution during the transition from fasting to feeding state. Fed animals regionally activate mTORC1 nutrient-sensing pathways in ISCs or ECs. Large intestine stem cells with robust mTORC1 activity exhibit large amounts of the Notch ligand Delta, promoting differentiation into the absorptive lineage.

Journal Reference:

  • Mattila, J., Viitanen, A., Fabris, G., Strutynska, T., Korzelius, J., & Hietakangas, V. (2024) Science Advances10(6). doi: 10.1126/sciadv.adi2671. https://www.science.org/doi/10.1126/sciadv.adi2671

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