HES1 regulates bone marrow mesenchymal stromal cell function by suppressing NFATc2-mediated inflammation

Area of Science:

• Hematology
• Stem Cell Biology
• Molecular Biology

Background:

• Hairy and enhancer of split-1 (HES1) is a Notch target gene regulating cell proliferation and differentiation.
• HES1 is crucial for hematopoiesis under stress conditions.
• The role of HES1 within the bone marrow (BM) microenvironment is not fully understood.

Purpose of the Study:

• To investigate the role of HES1 in regulating mesenchymal stromal cell (MSC) homeostasis within the BM niche.
• To determine HES1's function in supporting hematopoiesis.
• To elucidate the mechanisms by which HES1 influences MSCs and their supportive capacity.

Main Methods:

• Utilized a BM niche-specific Hes1 knockout mouse model (Hes1fl/flPrx1Cre).
• Assessed MSC frequency, self-renewal, and proliferation.
• Evaluated hematopoiesis supportive function in vitro and ex vivo.
• Performed transcriptome analysis and pharmacological interventions.
• Investigated HES1 binding to the NFATc2 promoter.

Main Results:

• HES1 is dispensable for steady-state hematopoiesis but crucial for MSCs under lipopolysaccharide (LPS) challenge.
• Hes1 deletion in BM reduces MSC frequency, self-renewal, and proliferation, impairing hematopoiesis support.
• HES1 deficiency alters expression of genes involved in cellular metabolism and inflammation.
• Pharmacological inhibition of inflammation rescues Hes1-deficient MSC phenotype and function.
• HES1 directly suppresses NFATc2-mediated inflammation by binding to its promoter.

Conclusions:

• HES1 plays a pivotal role in maintaining bone marrow MSC hemostasis.
• HES1 regulates MSCs' capacity to support hematopoiesis, particularly under inflammatory conditions.
• Targeting HES1-mediated inflammatory pathways may offer therapeutic strategies for hematopoiesis support.