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

Dhifaf Sarhan,Caroline Hallstrom,Jeffrey S Miller,Erica Warlick,Bartosz Grzywacz,Bruce R Blazar,Upasana Sunil Arvindam,Michael R Verneris,Jinhua Wang

doi:10.1172/jci.insight.130155

Abstract

Altered BM hematopoiesis and immune suppression are hallmarks of myelodysplastic syndrome (MDS). While the BM microenvironment influences malignant hematopoiesis, the mechanism leading to MDS-associated immune suppression is unknown. We tested whether mesenchymal stromal cells (MSCs) contribute to this process. Here, we developed a model to study cultured MSCs from patients with MDS (MDS-MSCs) compared with those from aged-matched normal controls for regulation of immune function. MDS-MSCs and healthy donor MSCs (HD-MSCs) exhibited a similar in vitro phenotype, and neither had a direct effect on NK cell function. However, when MDS- and HD-MSCs were cultured with monocytes, only the MDS-MSCs acquired phenotypic and metabolic properties of myeloid-derived suppressor cells (MDSCs), with resulting suppression of NK cell function, along with T cell proliferation. A MSC transcriptome was observed in MDS-MSCs compared with HD-MSCs, including increased expression of the ROS regulator, ENC1. High ENC1 expression in MDS-MSCs induced suppressive monocytes with increased INHBA, a gene that encodes for a member of the TGF-β superfamily of proteins. These monocytes also had reduced expression of the TGF-β transcriptional repressor MAB21L2, further adding to their immune-suppressive function. Silencing ENC1 or inhibiting ROS production in MDS-MSCs abrogated the suppressive function of MDS-MSC-conditioned monocytes. In addition, silencing MAB21L2 in healthy MSC-conditioned monocytes mimicked the MDS-MSC-suppressive transformation of monocytes. Our data demonstrate that MDS-MSCs are responsible for inducing an immune-suppressive microenvironment in MDS through an indirect mechanism involving monocytes.

Highlights

Myelodysplastic syndrome (MDS) is a clonal malignant disease of the hematopoietic stem cell
We found that both healthy donors (HDs)-mesenchymal stromal cells (MSCs) and MDS-MSCs were adherent to plastic and expressed the MSC markers CD73, CD90, CD105, and CD44 and lacked expression of the hematopoietic cell markers CD34 and MHCII (HLA-DR) (Figure 1A)
We found a significant increase in membrane-bound TGF-β expression on 7-day MDS-MSC–conditioned monocytes compared with control cultures with healthy donor MSCs (HD-MSCs) (Figure 5F)

Summary

Introduction

Myelodysplastic syndrome (MDS) is a clonal malignant disease of the hematopoietic stem cell. The role of MSCs in BM remains bidirectional, as they may directly alter the proliferation of CD34 hematopoietic stem cells and influence the BM immune compartments. They may activate the innate and adaptive immune system [4, 5]. Studies have shown that MSCs undergo molecular and genetic changes contributing to disease progression [6]. Other studies failed to show functional differences between MSCs from patients with MDS (MDS-MSCs) and healthy individuals [7, 8]

Methods

Results

Conclusion