@article{10.1172/jci.insight.130155, author = {Dhifaf Sarhan AND Jinhua Wang AND Upasana Sunil Arvindam AND Caroline Hallstrom AND Michael R. Verneris AND Bartosz Grzywacz AND Erica Warlick AND Bruce R. Blazar AND Jeffrey S. Miller}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell function}, year = {2020}, month = {3}, volume = {5}, url = {https://insight.jci.org/articles/view/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.}, number = {5}, doi = {10.1172/jci.insight.130155}, url = {https://doi.org/10.1172/jci.insight.130155}, }