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Inflammatory memory restrains intestinal stem cell regeneration.

Pavan Reddy1, Dongchang Zhao1, Visweswaran Ravikumar2

  • 1Baylor College of Medicine.

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|March 22, 2023
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Summary
This summary is machine-generated.

Inflammation from gastro-intestinal acute graft-versus-host disease (GI GVHD) causes lasting epigenetic changes in intestinal stem cells (ISCs). These "scarred" ISCs show reduced regenerative capacity, impacting future healing.

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Area of Science:

  • Gastroenterology and immunology
  • Stem cell biology
  • Epigenetics

Background:

  • Intestinal stem cells (ISCs) are crucial for gut health but face challenges during inflammatory diseases like graft-versus-host disease (GVHD).
  • How ISCs adapt to inflammation and whether these adaptations permanently alter their function remains unclear.

Approach:

  • Investigated Lgr5+ ISCs in clinically relevant models of gastro-intestinal acute GVHD.
  • Employed single-cell transcriptomics, organoid cultures, metabolic assays, epigenomic profiling, and in vivo studies.
  • Analyzed the functional and molecular consequences of inflammatory insults on ISC regeneration.

Key Points:

  • Inflammation induced metabolic alterations in ISCs, leading to succinate accumulation.
  • Succinate accumulation reprogrammed the epigenome of ISCs.
  • Epigenetic reprogramming impaired ISC differentiation and regeneration capacity in vitro.
  • These maladaptive changes persisted after the initial inflammatory insult.

Conclusions:

  • Gastro-intestinal GVHD leaves a persistent epigenetic memory in ISCs.
  • This 'scarring' affects ISC regeneration and adaptation to future stress.
  • Understanding this memory is critical for managing inflammatory gut diseases.