De-differentiation is key to intestine stem cell regeneration

Written by Freya Leask

Dana-Farber Cancer Institute scientists have settled the debate around the source of intestinal stem cells.

In new research published in Cell Stem Cell, scientists have uncovered the secret behind how stores of intestinal stem cells (ISCs) are restored after damage. A team from the Dana-Farber Cancer Center (MA, USA) discovered that, instead of calling on reserved cells following damage or depletion of ISC levels, already differentiated daughter cells are able to reverse course and become ISCs again.

ISCs sheltered in intestinal crypts generate billions of intestinal cells a day, protecting intestinal tissue from lasting damage caused by harmful or toxic substances which make their way to the gut. The constant cycle of cell death and replacement is a characteristic shared only by blood and skin tissue.

Stores of ISCs can also recover following depletion or damage, for example due to radioactivity. However, until now it was not understood how intestinal tissue was able to maintain the levels of ISCs which make this repair and regeneration possible.

“Our findings suggest that the restoration of intestinal stem cells occurs entirely by the process of de-differentiation,” commented the study’s senior author, Ramesh Shivdasani, (Dana-Farber Cancer Center, Brigham and Women’s Hospital and the Harvard Stem Cell Institute; all MA, USA). “We showed there’s no need for a reserve set of ISCs.”

In this study, a sample of ISCs and daughter cells were made to fluoresce through treatment with tamoxifen. After 48 hours, the ISCs were killed; however, subsequent ISCs found in the sample were also found to fluoresce, indicating they were previously labelled daughter cells which had ‘dedifferentiated’.  

“It also isn’t clear how the crypt knows that stem cells have died and need to be replaced,” Shivdasani remarked, “or how the daughter cells receive the signal to de-differentiate. This is a subject we’re currently exploring.”

Sources: Murata K, Jadhav U, Madha S et al. Ascl2-dependent cell dedifferentiation drives regeneration of ablated intestinal stem cells. Cell Stem Cell. doi:10.1016/j.stem.2019.12.011 (2020) (Epub ahead of print);…

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