Granulocytic myeloid-derived suppressor cells to prevent and treat murine immune-mediated bone marrow failure

Background and methods: Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells which originate in the bone marrow (BM) and have immunoregulatory functions. MDSCs have been implicated in the pathogenesis of several autoimmune diseases but not in immune aplastic anemia (AA). We examined the roles of granulocytic-MDSCs (G-MDSCs) in murine models of human AA and bone marrow failure (BMF). To perform Totalseq, bone marrow mononuclear cells were FACS sorted to obtain alive cells based on FSC and SSC from five bone marrow failure control mice and five G-MDSC-treated mice, mRNA profiles of single cells were generated and sequenced on an Illumina Novaseq System. Results: As both prophylaxis and therapy, BM-derived G-MDSCs improved pancytopenia and BM cellularity and decreased BM T cell infiltration in major histocompatibility (MHC)-matched CB10 BMF mice. Single cell RNA sequencing demonstrated that G-MDSCs downregulated cell cycle related pathways in BM infiltrated T cells, consistent with suppression of T cell proliferation by G-MDSCs. Conclusion: Our results demonstrate that BM-derived G-MDSCs improved pancytopenia and BM cellularity and decreased BM T cell infiltration in major histocompatibility (MHC)-matched CB10 BMF mice, but not in MHC-mismatched CByB6F1 BMF model. Therapeutic efficacy of G-MDSCs are immune context-dependent. Bone marrow mononuclear cells were FACS sorted to obtain alive cells based on FSC and SSC from five bone marrow failure control mice and five G-MDSC-treated mice. Overall design: We characterized transcriptomes in different cell populations based on their surface protein markers and marker genes in the bone marrow mononuclear cells from five C.B10 BM failure control mice and five bone marrow failure mice treated with G-MDSCs, and described gene expression of these cells.