Connecting energy metabolism to intestinal stem cell fate

A new study from the iCAN Digital Precision Cancer Medicine Flagship and just off the press in Gastroenterology reveals how energy metabolism controls intestinal stem cells and their differentiation.

The intestinal stem cells use cellular respiration for energy and produce progeny leading to all the six differentiated cell types in intestinal villi including food absorbing enterocytes and secretory cells. The study demonstrates how a small shift in the metabolic state of the intestinal stem cell determines the fate of its progeny.

“We observed this following targeted deletion of a key metabolic regulator Lkb1. This initiated a chain of molecular changes attenuating cellular respiration which in turn switched on a promoter of secretory differentiation,” says Yajing Gao, one of the lead authors finishing her doctoral studies in Tomi Mäkelä’s lab.

The results reveal that stem cell intrinsic energy metabolism controls intestinal stem cell fate.

“Earlier this was considered to be controlled mostly by factors from the neighboring microenvironment,” comments lead and corresponding author Yan Yan.

“This work was a great collaboration with the Katajisto lab at University of Helsinki and Clevers lab at Hubrecht Institute in the Netherlands nd opens interesting questions for example regarding whether this mechanism is deregulated in cancer cells.”

Gao Y, Yan Y, Tripathi S, Pentinmikko N, Amaral A, Päivinen P, Domènech Moreno E, Andersson S, Wong IPL, Clevers H, Katajisto P, Mäkelä TP: LKB1 Represses ATOH1 via PDK4 and Energy Metabolism and Regulates Intestinal Stem Cell Fate. Gastroenterology. https://doi.org/10.1053/j.gastro.2019.12.033

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