STAT1 regulates immune-mediated intestinal stem cell proliferation and epithelial regeneration Journal Article
| Authors: | Takashima, S.; Sharma, R.; Chang, W.; Calafiore, M.; Fu, Y. Y.; Jansen, S. A.; Ito, T.; Egorova, A.; Kuttiyara, J.; Arnhold, V.; Sharrock, J.; Santosa, E.; Chaudhary, O.; Geiger, H.; Iwasaki, H.; Liu, C.; Sun, J.; Robine, N.; Mazutis, L.; Lindemans, C. A.; Hanash, A. M. |
| Article Title: | STAT1 regulates immune-mediated intestinal stem cell proliferation and epithelial regeneration |
| 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. © The Author(s) 2024. |
| Keywords: | immunohistochemistry; controlled study; human tissue; protein expression; genetics; nonhuman; flow cytometry; cell proliferation; t lymphocyte; t-lymphocytes; animal cell; mouse; animal; cytology; metabolism; animals; mice; mice, knockout; animal tissue; stat1 protein; immune system; gene expression; animal experiment; animal model; transplantation; transcriptomics; mice, inbred c57bl; immunoregulation; c57bl mouse; stem cell; regeneration; rna; gastrointestinal toxicity; immunology; whole body radiation; gamma interferon; chromatin immunoprecipitation; myc protein; graft versus host reaction; tamoxifen; stem cells; real time polymerase chain reaction; upregulation; cell regeneration; interferon-gamma; t cell depletion; bone marrow transplantation; graft vs host disease; small intestine; proto-oncogene proteins c-myc; intestine cell; tissue injury; transcriptome; t lymphocyte activation; immunocompetent cell; knockout mouse; goblet cell; intestine crypt; intestine mucosa; coculture; cell; wnt signaling; correlation; paneth cell; intestinal mucosa; minor histocompatibility antigen; stat1 transcription factor; intestine epithelium; gamma interferon receptor; intestinal stem cell; hemagglutinin; secretory cell; three-dimensional imaging; myc protein, mouse; human; female; article; organoids; stat1 protein, mouse; gene set enrichment analysis; organoid; duodenoscopy; single cell rna seq; intestinal organoid; tuft cell; interferon gamma receptor |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-01-02 |
| Start Page: | 138 |
| Language: | English |
| DOI: | 10.1038/s41467-024-55227-5 |
| PUBMED: | 39746933 |
| PROVIDER: | scopus |
| PMCID: | PMC11697299 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Alan Hanash -- Source: Scopus |
