A cell lineage-intrinsic decision balances terminal cell fate

EU-LIFE Science Newsletter 3/2017

News from the Institut Curie (IC), France

Many adult tissues renew terminally differentiated cell types. How are balanced numbers of cell populations are achieved? A new study from the Institut Curie (in press, EMBOJ) uncovers a lineage-intrinsic mechanism required for enteroendocrine cell fate specification during tissue homeostasis in the fly intestine.

Allison Bardin’s team (Stem Cells and Tissue Homeostasis - Inserm/CNRS/Institut Curie) studies cell fate decisions of stem cells using the intestine of the fruit fly as a model system. Adult organs contain terminally differentiated cells that perform critical functions within the tissue. As these cells become damaged, they are often replenished through the activity of tissue-specific stem cells. Intriguingly, different cell types must be present at certain proportions within the organ to allow optimal function. How is this achieved? How does the stem cell know which cell type to produce? Importantly, the correct balance of cell types must be not only established during development, but maintained during tissue renewal.

The Bardin team’s recent study (in press, EMBOJ, DOI: 10.15252/embj.201695622) investigates how enteroendocrine cells are replenished from stem cells during tissue homeostasis in the adult fly intestine. The fly intestine is composed largely of absorptive enterocytes with secretory enteroendocrine cells (EE cells) being only 10% of the terminally differentiated cells. How then, is this rare population of cells maintained by the stem cells? Could a negative feedback signal emitted from EE cells inhibit their own production? The data argue against this idea: using genetic strategies, the authors demonstrate that neither the loss nor the gain of EE cells alters EE cell densities in neighboring tissue. Instead, a lineage-intrinsic mechanism requiring the endocytic regulator Numb to inhibit Notch signaling is at work. Numb itself is segregated both symmetrically and asymmetrically during intestinal stem cell division. The alteration of cell polarity factors, which change Numb segregation and activity, can modify EE numbers suggesting that this inheritance may initiate a cell fate decision. Interestingly, Numb segregation is not sufficient and the continued expression of Numb is also required for EE cell differentiation. Thus, this study demonstrates that in the absence of extrinsic feedback signaling, lineage-intrinsic regulation can produce the correct output of cell fates in a homeostatic tissue.

Original article: Sallé J, Gervais L, Boumard B, Stefanutti M, Siudeja K, Bardin A.J. (2017) Intrinsic regulation of enteroendocrine fate by Numb. EMBO Journal (in Press) 

Image: Enteroendocrine cell (red) fate requires Numb-mediated Notch inhibition. Image: Allison Bardin, Institut Curie