The small intestine is a vital organ responsible for absorbing nutrients from food and serving as a barrier against pathogens. Due to constant exposure to food, chemicals and microorganisms, intestinal cells must be continuously replaced to keep the organ healthy. Intestinal stem cells are responsible for regenerating the intestinal epithelium by constantly dividing and giving rise to the different specialized cell types that maintain the organ function.
A research group led by Professor Pekka Katajisto from the Centre of Excellence of Stem Cell Metabolism, University of Helsinki, has discovered a new type of intestinal stem cell, which is particularly important during repair of the intestine upon damage, due to its increased ability to form a certain type of specialized cell, called Paneth cell. In the future, the finding could have implications for designing chemoprotective treatments especially for elderly patients.
In the study led by doctoral researcher Simon Andersson, the group generated a new mouse model and labelling approach that allowed them to distinguish intestinal stem cells based on the properties of their mitochondria, an organelle which is important for cell metabolism and function.
“We found that a subset of intestinal stem cells, which are otherwise similar to the rest of the stem cells, have metabolically distinct mitochondria”, Andersson explains.
This metabolic difference activates enzymes that regulate gene expression, which ultimately leads to the stem cell differentiating into a Paneth cell.
“Paneth cells have an important role in supporting stem cell activity, and thus intestinal regeneration”, Katajisto clarifies.
When cultured in the laboratory, this metabolically distinct type of intestinal stem cells regenerates, or form self-organized 3D tissues called organoids, better due to their ability to generate Paneth cells that support their function.
In the mouse this metabolic signal leads to replacement of old Paneth cells with new ones. This is particularly important in old animals where old Paneth cells are defective and unable to support the stem cells, leading to reduced regeneration especially upon intestinal injury, for example due to chemotherapeutic treatment.
“By mimicking the metabolism of this subpopulation of stem cells that contain distinct mitochondria, we were able to support intestinal regeneration of old mice so that they recover from the chemotherapy-induced side effects as well as young animals”, Andersson explains.
“If this works similarly in humans, because gastrointestinal complications are among the most common and dose limiting adverse-effects of many chemotherapeutics, in the future we might be able to alleviate side effects that damage the intestine in elderly patient by simply administering a naturally occurring metabolite while they undergo chemotherapy”, Katajisto summarizes.
Original publication:
Andersson, S., Bui, H., Viitanen, A. et al. Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells. Nat Metab (2025)