STAT1 regulates immune-mediated intestinal stem cell proliferation and epithelial regeneration

Shuichiro Takashima, Roshan Sharma, Winston Chang, Marco Calafiore, Ya-Yuan Fu, Suze A. Jansen, Takahiro Ito, Anastasiya Egorova, Jason Kuttiyara, Viktor Arnhold, Jessica Sharrock, Endi Santosa, Ojasvi Chaudhary, Heather Geiger, Hiromi Iwasaki, Chen Liu, Joseph Sun, Nicolas Robine, Linas Mazutis, Caroline A. Lindemans and Alan M. Hanash ()
Additional contact information
Shuichiro Takashima: Memorial Sloan Kettering Cancer Center
Roshan Sharma: New York Genome Center
Winston Chang: Memorial Sloan Kettering Cancer Center
Marco Calafiore: Memorial Sloan Kettering Cancer Center
Ya-Yuan Fu: Memorial Sloan Kettering Cancer Center
Suze A. Jansen: Utrecht University
Takahiro Ito: Memorial Sloan Kettering Cancer Center
Anastasiya Egorova: Memorial Sloan Kettering Cancer Center
Jason Kuttiyara: Memorial Sloan Kettering Cancer Center
Viktor Arnhold: Memorial Sloan Kettering Cancer Center
Jessica Sharrock: Memorial Sloan Kettering Cancer Center
Endi Santosa: Memorial Sloan Kettering Cancer Center
Ojasvi Chaudhary: Memorial Sloan Kettering Cancer Center
Heather Geiger: New York Genome Center
Hiromi Iwasaki: Fukuoka
Chen Liu: Yale School of Medicine
Joseph Sun: Memorial Sloan Kettering Cancer Center
Nicolas Robine: New York Genome Center
Linas Mazutis: Memorial Sloan Kettering Cancer Center
Caroline A. Lindemans: Utrecht University
Alan M. Hanash: Memorial Sloan Kettering Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The role of the immune system in regulating tissue stem cells remains poorly understood, as does the relationship between immune-mediated tissue damage and regeneration. Graft vs. host disease (GVHD) occurring after allogeneic bone marrow transplantation (allo-BMT) involves immune-mediated damage to the intestinal epithelium and its stem cell compartment. To assess impacts of T-cell-driven injury on distinct epithelial constituents, we have performed single cell RNA sequencing on intestinal crypts following experimental BMT. Intestinal stem cells (ISCs) from GVHD mice have exhibited global transcriptomic changes associated with a substantial Interferon-γ response and upregulation of STAT1. To determine its role in crypt function, STAT1 has been deleted within murine intestinal epithelium. Following allo-BMT, STAT1 deficiency has resulted in reduced epithelial proliferation and impaired ISC recovery. Similarly, epithelial Interferon-γ receptor deletion has also attenuated proliferation and ISC recovery post-transplant. Investigating the mechanistic basis underlying this epithelial response, ISC STAT1 expression in GVHD has been found to correlate with upregulation of ISC c-Myc. Furthermore, activated T cells have stimulated Interferon-γ-dependent epithelial regeneration in co-cultured organoids, and Interferon-γ has directly induced STAT1-dependent c-Myc expression and ISC proliferation. These findings illustrate immunologic regulation of a core tissue stem cell program after damage and support a role for Interferon-γ as a direct contributor to epithelial regeneration.

Date: 2025
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DOI: 10.1038/s41467-024-55227-5

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