HSCI scientists identify where intestinal stem cells come from
The human intestine has the powerful ability to renew itself and recover from damage. Intestinal stem cells (ISCs), lodged in pockets of tissue called crypts, generate the cells that continuously repopulate the intestinal lining. Even the stem cells themselves have a safety net: when they’re damaged, healthy replacements appear in less than a week.
For years, scientists have debated how the ISCs’ re-emergence occurs. Some have thought that the intestine keeps a pool of ISCs on reserve – a kind of backup-backup supply – to replenish the front-line ISCs that have been lost. Others have thought that something more complicated is happening: The ISCs give rise to more specialized, or “differentiated,” offspring – daughter cells that form the inner lining of the intestine. When the ISCs are damaged, the daughter cells reverse course and “de-differentiate,” reverting into the ISCs from which they arose.
A new study by HSCI scientists comes down solidly on the latter explanation. Published in the journal Cell Stem Cell, the researchers found that ISCs and their daughter cells have a strikingly reciprocal relationship: under normal conditions, ISCs differentiate into daughter cells, and, if the ISCs are lost, the daughter cells simply reverse course and become ISCs.
“Our findings suggest that the restoration of intestinal stem cells occurs entirely by the process of de-differentiation. We showed there’s no need for a reserve set of ISCs,” said the study’s senior author Ramesh Shivdasani, M.D., Ph.D., HSCI Principal Faculty member and professor of medicine at Dana-Farber Cancer Institute.
To determine how ISCs are restored, Shivdasani and his collaborators performed a time-lapse experiment in mice. They labeled ISCs so that the cells and their offspring would become fluorescent. They waited 48 hours for the label to take hold, then killed the ISCs. If the daughter cells were indeed de-differentiating, any ISC cells produced after that point would be fluorescent. That’s exactly what researchers found.
While scientists have been able to convert many kinds of differentiated cells into stem cells using laboratory techniques, Shivdasani and his colleagues’ discovery demonstrates that de-differentiation is more than just a laboratory curiousity; it is the primary way that damaged stem cells are naturally restored in the intestine. It’s not known whether cells in other organs and tissues have this capability, but it remains an open avenue of investigation.
“It also isn’t clear how the crypt knows that stem cells have died and need to be replaced,or how the daughter cells receive the signal to de-differentiate.” Shivdasani said. “This is a subject we’re currently exploring.”
This story was originally published on the Dana-Farber Cancer Institute website on February 20, 2020, under the title “A case of reverse development: Dana-Farber scientists solve long-debated puzzle of how the intestine heals itself.”
Source article: Murata, K. et al. (2020). Ascl2-Dependent Cell Dedifferentiation Drives Regeneration of Ablated Intestinal Stem Cells. Cell Stem Cell. DOI: 10.1016/j.stem.2019.12.011
Funding: The research was supported by the National Institutes of Health and gifts from the Lind family.