by Leibniz Institute on Aging

Stem cells are essential for homeostasis and cell renewal in organs like skin, lung or intestine. During the course of life, their function decreases steadily, making this decline a main factor for the development of age-associated diseases. Researchers of the Leibniz Institute on Aging in Jena, Germany, and their colleagues of the Buck Institute for Research on Aging in Novato, U.S., investigated the mechanisms of intestinal cell renewal in the model organism Drosophila. Their results show that the transcription factor Klumpfuss plays a key role in this process by precisely regulating the differentiation of cell types in the fly intestine.

Stem cells react to tissue damage with an increase in their proliferation rate, leading to the production of new differentiated cells. Balance between cell loss and cell renewal through strict control of stem cell division guarantees the maintenance of organ size and function. Precise control of differentiation in adult stem cell lines is important for the development and maintenance of tissue homeostasis. Stem cell dysfunction can disturb this process, which can lead to tissue degeneration and cancer.

The researchers studied the differentiation of adult stem cells during tissue homeostasis in the midgut of the fruit fly (Drosophila melanogaster) because it bears many similarities with the human gastrointestinal tract in both structure and function. Injuries or infections lead to damage of the intestinal mucosa, which results in an increase in proliferation and differentiation of the intestinal stem cells (ISCs) to replace damaged cells and restore homeostasis. Disruption of normal cell differentiation leads to impairment of intestinal function, as can be observed in the aging intestine. How cell differentiation is exactly regulated has not been known yet.

Researchers of the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI) in Jena, Germany, together with colleagues of the Buck Institute for Research on Aging in Novato, U.S., have identified a novel player in the regulation of cell renewal and differentiation in the midgut of the model organism Drosophila. “With its stem cells, the intestine is able to regenerate itself continuously and to ensure the function and integrity of the tissue during the lifespan of an organism,” says Dr. Jerome Korzelius, first author of the study published in Nature Communications.

Asymmetric cell division of intestinal stem cells

Asymmetric division of ISCs is crucial for the process of cell renewal. An ISC renews by dividing into another stem cell and an enteroblast (EB) daughter cell. This daughter cell can then differentiate into two different types of differentiated cells depending on signaling cues: absorptive enterocytes (EC), cells that take up nutrients and are responsible for immune defense or enteroendocrine cells (EE) that produce gastrointestinal hormones. Recent work has shown that lineage choice in these EB daughter cells is likely more complex than previously thought.

Transcription factor Klumpfuss as regulator

The researchers discovered that the transcription factor Klumpfuss (Klu), which is related to the mammalian tumor-suppressor gene “Wilms’ Tumor 1” (WT1), plays an important role in the adult Drosophila midgut for the lineage choice of EBs. “We found Klu to be expressed specifically in EBs to regulate cellular differentiation towards the enterocyte lineage,” tells Dr. Korzelius, who is currently working at the Max Planck Institute for Biology of Ageing in Cologne, Germany. Klu suppresses the differentiation of enteroendocrine cells from EBs by downregulating genes necessary for EE differentiation. Therefore, a loss of Klu in the enteroblasts leads to differentiation of EBs in EE cells.

Interplay with Notch signaling

Furthermore, the researchers found that Klu and Notch signaling together play a role in ISC division and differentiation. ISCs produce the Notch-ligand Delta and activate Notch in the enteroblast daughter cell, the precursor of mature enterocytes. Loss of Notch in ISC lineages leads to the development of tumors, likely because of impaired EB differentiation that leads to an increased frequency of symmetric divisions and excess EE differentiation. During EB differentiation, the transcription factor Klu acts to control Notch target gene expression. This control of Notch target genes by Klu adds another layer of regulation to this complex pathway, which is also important in many diseases in humans.

“Our results give a mechanistic insight into how cell differentiation in the Drosophila intestine is regulated,” says Dr. Heinrich Jasper, senior author of the study. These are important insights into the control mechanisms of tissue regeneration that are also relevant for mammals, including humans.

Provided by Leibniz Institute on Aging