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

Area of Science:

• Immunology
• Stem Cell Biology
• Gastroenterology

Background:

• The interplay between the immune system and tissue stem cells, particularly in damage and regeneration, is not fully understood.
• Graft versus host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) causes immune-mediated intestinal epithelial damage and impacts the stem cell compartment.

Purpose of the Study:

• To investigate the impact of T-cell-driven injury on intestinal stem cells (ISCs) and epithelial regeneration.
• To elucidate the role of STAT1 and Interferon-γ signaling in the epithelial response to GVHD.

Main Methods:

• Single-cell RNA sequencing of intestinal crypts from mice undergoing experimental BMT.
• Genetic deletion of STAT1 and Interferon-γ receptor in the murine intestinal epithelium.
• Co-culture of intestinal organoids with activated T cells.

Main Results:

• Intestinal stem cells (ISCs) in GVHD mice showed increased Interferon-γ response and STAT1 upregulation.
• STAT1 deficiency or Interferon-γ receptor deletion in the epithelium reduced proliferation and impaired ISC recovery post-allo-BMT.
• STAT1 expression in ISCs correlated with c-Myc upregulation; Interferon-γ directly induced STAT1-dependent c-Myc expression and ISC proliferation.

Conclusions:

• Interferon-γ directly regulates a core tissue stem cell program following immune-mediated damage.
• STAT1 is a critical mediator of epithelial regeneration and ISC recovery in response to Interferon-γ signaling after allo-BMT.