Two research teams have illuminated unique roles in intestinal regeneration for two distinct stem cell populations found on the inner surface of the intestine. The inner lining of the intestine plays an essential role in absorption of nutrients and balancing absorption and secretion of water and electrolytes, as well as providing a barrier against entry of bacteria. The lining is only one cell thick and cells slough off the surface continuously, lasting only about 1 week, requiring a process of continuous regeneration. Cells are also replaced following any injury. Recently, two populations of intestinal stem cells that are necessary for regeneration were identified by their different locations in the intestinal surface, as well as the unique proteins marking their outer membranes—either Lgr5 or Bmi1. Two research teams took a closer look at these stem cells to characterize their roles in intestinal regeneration.
One of the teams conducted research as part of the NIDDK’s Intestinal Stem Cell Consortium. Using a microscopic technique that highlights intestinal stem cells with fluorescent markers for Lgr5 and Bmi1 in genetically modified mice, the researchers measured proliferation of the cells under normal, healthy conditions, as well as after injury caused by radiation. They found that the stem cells with Lgr5 on their surface actively proliferated under normal conditions but were destroyed by radiation. The stem cells marked by Bmi1 were relatively inactive under normal conditions but resisted radiation and proliferated dramatically following the injury. The Bmi1-marked stem cells in culture could also form some Lgr5-marked stem cells, showing their capacity to repopulate the intestine with both stem cell populations following injury.
Another team examined whether the Paneth cell, another type of intestinal cell located near Lgr5 stem cells, was essential for the ability of Lgr5 stem cells to repopulate the intestinal lining as part of normal cell turnover and tissue renewal. Paneth cells are known for secreting substances, such as proteins with antimicrobial properties, enzymes, and growth factors. Considering their proximity to intestinal stem cells, Paneth cells were thought to be involved in stem cell functions. This study used genetically modified mice and fluorescent markers to identify the Lgr5-producing stem cells and Paneth cells during early intestinal development. They found that the appearance of the intestinal stem cells preceded Paneth cells in the developmental process, and that the stem cells appeared to function normally. They then created a genetically modified mouse that lacked Paneth cells. The stem cells functioned normally in this mouse model as well, proliferating to renew the intestinal surface as usual. These experiments indicate that Paneth cells are not essential for many aspects of Lgr5-marked stem cell function, though Paneth cells may still have other beneficial effects on their neighboring stem cells.
Taken together, the work of these two research teams paints a more nuanced picture of the complementary stem cell types that renew the intestinal surface throughout life, in terms of continuing cell turnover as well as regeneration following injury. This knowledge could be applied to optimizing recovery from different forms of intestinal injury.
Kim T-H, Escudero S, and Shivdasani RA. Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells. Proc Natl Acad Sci USA 109: 3932-3937, 2012.
Yan KS, Chia LA, Li X, et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci USA 109: 466-471, 2012.