Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell...

Area of Science:

• Immunology
• Hematology
• Cell Biology

Background:

• Myelodysplastic syndromes (MDS) are characterized by altered bone marrow (BM) hematopoiesis and immune suppression.
• The BM microenvironment's role in malignant hematopoiesis is recognized, but the mechanism of MDS-associated immune suppression remains unclear.
• Mesenchymal stromal cells (MSCs) are key components of the BM microenvironment, and their potential contribution to immune suppression in MDS was investigated.

Purpose of the Study:

• To investigate whether mesenchymal stromal cells (MSCs) from patients with myelodysplastic syndrome (MDS) contribute to immune suppression.
• To elucidate the mechanism by which MDS-MSCs might induce an immune-suppressive microenvironment.
• To compare the function and characteristics of MSCs from MDS patients (MDS-MSCs) with those from healthy donors (HD-MSCs).

Main Methods:

• Development of a co-culture model to study interactions between MSCs and monocytes.
• Phenotypic and metabolic characterization of MDS-MSCs and HD-MSCs.
• Transcriptome analysis of MSCs to identify differentially expressed genes.
• Functional assays assessing the impact of MSCs on NK cell function and T cell proliferation.
• Gene silencing experiments (ENC1, MAB21L2) and reactive oxygen species (ROS) inhibition.

Main Results:

• MDS-MSCs, but not HD-MSCs, acquired myeloid-derived suppressor cell (MDSC)-like properties when co-cultured with monocytes, leading to suppression of NK and T cell functions.
• Transcriptome analysis revealed increased expression of the ROS regulator ENC1 in MDS-MSCs.
• High ENC1 expression in MDS-MSCs induced suppressive monocytes with increased INHBA and reduced MAB21L2 expression.
• Silencing ENC1 or inhibiting ROS in MDS-MSCs abrogated monocyte-mediated suppression.
• Silencing MAB21L2 in monocytes co-cultured with HD-MSCs mimicked the suppressive phenotype observed with MDS-MSCs.

Conclusions:

• Mesenchymal stromal cells (MSCs) from MDS patients are responsible for inducing an immune-suppressive microenvironment in MDS.
• This immune suppression is mediated indirectly through the transformation of monocytes into suppressive cells.
• The mechanism involves increased ENC1 expression, ROS production, and altered TGF-β signaling (INHBA and MAB21L2) in MDS-MSCs, leading to monocyte reprogramming.