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Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway

Srdjan Grusanovic1,2,3, Petr Danek1, Maria Kuzmina1,2

  • 1Department of Hemato-Oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.

EMBO Reports
|November 7, 2022
PubMed

Insights

Chronic inflammation impairs hematopoietic stem cell (HSC) function by altering their gene expression and inflammatory profile. Stat3 pathway inhibition rescues HSC fitness, offering potential therapeutic targets.

Area of Science:

  • Hematology
  • Immunology
  • Stem Cell Biology

Background:

  • Chronic inflammation poses significant health risks, impacting various tissues and organs.
  • Emerging evidence links chronic inflammation to altered hematopoiesis, but the precise mechanisms affecting hematopoietic stem cells (HSCs) remain unclear.

Purpose of the Study:

  • To investigate the mechanistic effects of chronic inflammation on HSCs using a mouse model.
  • To identify key molecular mediators and signaling pathways involved in inflammation-induced HSC dysfunction.

Main Methods:

  • Utilized a mouse model of chronic multifocal osteomyelitis (CMO) to induce sustained inflammation.
  • Analyzed hematopoietic and non-hematopoietic bone marrow compartments for HSC alterations.
  • Assessed HSC function, gene expression profiles, and inflammatory markers.
  • Investigated the role of Interleukin-6 (IL-6) and the Janus kinase/Signal transducer and activator of transcription 3 (Jak/Stat3) signaling pathway.

Main Results:

  • CMO induced HSC expansion and impaired function, with contributions from both hematopoietic and non-hematopoietic bone marrow cells.
  • The CMO environment imprinted a myeloid gene signature and pro-inflammatory profile onto HSCs.
  • IL-6 and Stat3 were identified as critical mediators; IL-6 and Stat3 blockage reduced HSC numbers.
  • Only Stat3 activity inhibition significantly restored HSC fitness, decoupling it from typical osteomyelitis features.

Conclusions:

  • Chronic inflammation detrimentally affects HSC function and number through mechanisms involving IL-6 and Stat3 signaling.
  • Targeting the Stat3 pathway holds promise for rescuing HSC fitness in inflammatory conditions.
  • These findings open new therapeutic avenues for treating stem cell dysfunction in chronic inflammatory diseases.

Keywords:
IL-6/Jak/Stat3chronic inflammationchronic multifocal osteomyelitishematopoietic stem cellsniche

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