Connective tissue cells in the mouse intestinal regions most severely damaged by immune attack activate a gene for an enzyme that activates thyroid hormone; in culture, the active hormone promotes the development of stem cell-derived “mini-guts”

Connective tissue cells in the mouse intestinal regions most severely damaged by immune attack activate a gene for an enzyme that activates thyroid hormone; in culture, the active hormone promotes the development of stem cell-derived “mini-guts”

Pavan Reddy’s group at Baylor College of Medicine posted a preprint, an article that has yet to undergo peer review, on 16 October. The researchers transplanted bone marrow and T-cells from genetically mismatched donors into mice. A week later, they mapped gene activity in 6,2 million cells of the small intestine and found fibroblasts, which are connective tissue cells, expressing Dio2 and Il11 in the most severely damaged regions.

After a bone marrow transplant, donor T-cells sometimes attack the recipient’s tissues, including the intestine, causing graft-versus-host disease. Stem cells at the base of crypts, small pockets in the intestinal wall, renew the intestinal lining. Nearby Paneth cells and fibroblasts provide a supportive environment called a niche. T-cells kill stem cells and Paneth cells, disrupting the niche. As Reddy’s group showed in 2024, surviving stem cells retain a memory of inflammation and have a reduced capacity to recover. The researchers investigated whether another niche forms where the original one has been destroyed.

Affected mice had fewer stem cells than control mice that received transplants from genetically identical donors, and gene activity indicated that supportive signals from fibroblasts were absent. Dio2 was particularly active in the most severely damaged regions of the lower small intestine, although the authors had not specifically set out to investigate it. This gene encodes an enzyme that converts the thyroid hormone thyroxine into its active form, T3. In the absence of severe injury, Dio2 is expressed only in a subset of intestinal neurons. Here, however, fibroblasts activated Dio2 together with Il11, the gene encoding the signaling protein interleukin-11. T3 levels in this part of the intestine were higher in affected mice than in controls.

A 2021 study showed that T3 changes the number and activity of intestinal stem cells. The authors tested its effects in organoids, “mini-guts” grown from crypts. A T3 receptor blocker suppressed budding, the formation of outgrowths, and reduced organoid size, whereas T3 increased budding. Interleukin-11 administered to mice reduced mortality from graft-versus-host disease in 1999 experiments; in the organoids, it enhanced the effect of T3. Under stress induced by interferon-gamma, a protein through which T-cells kill stem cells, T3 and interleukin-11 each preserved budding and organoid size, with the strongest protection provided by the combination.

The authors propose that a neural signal could activate Dio2 through cAMP, an intracellular messenger. Dio2 depends on cAMP in brown adipose tissue. In these fibroblasts, a gene encoding an enzyme that produces cAMP was active, while intestinal neurons in the same region showed increased activity of genes associated with sympathetic neurons. Forskolin, which raises cAMP levels, activated Dio2 and Il11 in cultured intestinal fibroblasts.

The authors conclude that the tissue builds a new niche where the original one has broken down: fibroblasts expressing Dio2 and Il11 supply surviving stem cells with T3 and interleukin-11. These fibroblasts were also found in mice with colitis and in published data on Crohn’s disease.

Discussing treatment, the authors write (CD3 is a T-cell marker):

Our data suggest that suppressing CD3⁺ cell cytotoxicity is necessary, but may be insufficient if Dio2⁺ Il11⁺ fibroblasts cannot supply the factors that support stem cells.

They suggest that restoring local T3 and interleukin-11 could complement immunosuppression. Interleukin-11 is also known to promote scarring. The authors suggest that chronic graft-versus-host disease may begin during the acute phase: if repair by these fibroblasts persists, it may shift from healing to scar formation.