DECTIN1+ myeloid-derived suppressor cells mediate therapeutic effect of MSCs in haplo-HSCT for severe aplastic anemia

Abstract Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder marked by pancytopenia and marrow hypoplasia. As a promising therapeutic option, haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is still limited by graft rejection and delayed immune reconstitution, which can be effectively mitigated by mesenchymal stem cell (MSC) coinfusion. Here, we demonstrated that haplo-HSCT significantly restored the proportion and immunosuppressive capacity of bone marrow myeloid-derived suppressor cells (MDSCs) in SAA patients, and DECTIN1 + MDSCs emerged as central immunoregulators. MSC coinfusion further enhanced this effect. Mechanistically, MSC-derived exosomal ANXA2 upregulated DECTIN1 expression in MDSCs, which in turn activated STAT3 signaling to increase TNFAIP3 expression, thereby suppressing inflammatory T-cell responses. These changes were also reflected in peripheral blood. Human bone marrow organoid experiments confirmed that MSC coinfusion promoted DECTIN1 + MDSC expansion and accelerated bone marrow microenvironment recovery. Our findings revealed a previously unrecognized MSC-mediated mechanism and highlighted DECTIN1 + MDSCs as key immunoregulatory mediators and potential therapeutic targets in SAA.