With an absorptive surface area said to be the size of a studio apartment, the small intestine has the critical job of internalizing nutrients from our food. Thanks to an abundance of intestinal stem cells (ISCs), it’s also one of the most rapidly renewing organs in the body—regenerating quickly from the constant contact with digested food and harsh acidic gastric juices.
However, stem cell researchers are still seeking answers to some long-standing questions around the nature of ISCs. For instance, what are the origins of these cells, and how do they respond to damage in the intestinal lining?
According to Nick Barker, Research Director at A*STAR’s Institute of Molecular and Cell Biology (IMCB), knowing such information would be a fundamental starting point in efforts to harness the therapeutic potential of stem cells for treating chronic gut conditions.
Previously, Barker’s team had pinpointed the cell surface receptor called Lgr5 as an ISC biomarker. However, a subsequent study performed by another group of researchers observed no obvious change following the selective destruction of the small intestine’s Lgr5-positive cells every other day—causing them to hypothesize that this subpopulation was not a primary driver of epithelial regeneration.
In the current study, Barker and his colleagues revisited this decade-old hypothesis, and developed a genetically engineered mouse model in which Lgr5-positive ISCs were completely depleted. A closer look at the structure and function of the small intestine in these animals revealed stark differences compared to their control counterparts. After a few days, the small intestines of mice lacking Lrg5-positive ISCs started breaking down, causing the animals to bleed excessively. Many of the Lrg5-negative mice did not survive.
The scientists also used another experimental model to test their hypothesis: miniaturized and simplified lab-grown versions of intestinal tissues. They demonstrated that wiping out Lgr5-positive ISCs in these epithelial organoids significantly compromised their structural architecture, leading to the destruction of intestinal tissues.
Together, these findings support a new paradigm in the stem cell field—that Lrg5-positive cells are indispensable to the health and integrity of the intestinal epithelium. According to Barker, the team has their specialized mouse model to thank for these ground-breaking results.
“The model facilitates the complete ablation of Lgr5-positive stem cell compartments as a means of evaluating their contributions to epithelial homeostasis, repair, and disease,” explained Barker, adding that the partial elimination of Lgr5-positive ISCs in previous studies may have enabled new epithelial cells to form.
Ultimately, their model can facilitate future studies on everything from cancer biology to drug development. “We expect that this model will be instrumental in helping to establish the functional importance of both regular stem cells and cancer stem cells, as an essential pre-requisite to validating their value in regeneration medicine and cancer treatment applications,” concluded Barker.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and Singapore Immunology Network (SIgN).
