Inflammation has lasting effects on intestinal stem cells, researchers find

Researchers from Baylor College of Medicine, the University of Michigan, and collaborating institutions have found that intestinal inflammation leaves long-term scars on intestinal stem cells (ISCs) that reduce their ability to heal the gut, even after the inflammation has subsided. This finding is important because it affects how ISCs respond to future challenges. The study is published in Stem cell.

“We study graft-versus-host disease (GVHD), a major cause of death after bone marrow transplantation, a potentially curative therapy for many blood diseases. One of our goals is to better understand GVHD and identify strategies to control it,” said corresponding author Dr. Pavan Reddy, professor and director of the Dan L Duncan Comprehensive Cancer Center at Baylor and formerly at the University of Michigan.

“GVHD is an inflammatory reaction in which immune T cells from the bone marrow transplant donor attack the host’s intestinal cells, primarily ISCs,” said first author Dr. Dongchang Zhao, in Reddy’s lab.

Although many ISCs die during GVHD, survivors remain. However, it is unclear whether they are fully functional or can regain full functionality after GVHD resolution, which has fundamental implications for host resilience and repair.

“In the current study, we investigated the consequences of inflammation on embryonic stem cells (ESCs) in clinically relevant and well-defined models of GVHD,” Reddy said.

“Using cellular and animal models, we found that exposure to inflammation caused ISCs to alter their metabolism in a way that led to the accumulation of succinate, a product of cellular processes, which in turn reprogrammed the epigenome,” Zhao said.

The epigenome is a system of chemical marks on DNA that regulates which genes are expressed by the cell. Inflammation-induced reprogramming of the epigenome altered the expression of genes involved in cell reproduction. Overall, the reprogrammed embryonic stem cells were less able to regenerate, a first step toward healing the gut.

“We then studied whether embryonic stem cells would be able to recover their regenerative capacity after the inflammation resolved,” Reddy said.

“We found that embryonic stem cells did not overcome their initial exposure to inflammation. Despite attenuating GVHD-related inflammation for 28 days, embryonic stem cells retained reduced regenerative capacity that led to poor recovery and increased mortality from challenges such as non-lethal radiation exposure in animal models. Further research is underway to design strategies to help embryonic stem cells “forget” their encounter with inflammation and build resilience to immune attacks.”

Other contributors to this work include Visweswaran Ravikumar, Tyler J. Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T. Keller, Fengju Chen, Laure Maneix, Robert R. Jenq, Robert Britton, Katherine Y. King, Ana E. Santibanez, Chad J. Creighton, and Arvind Rao. The authors are affiliated with the University of Michigan Baylor College of Medicine and the University of Texas MD Anderson Cancer Center at Houston.