IL-10 Signaling Restricts Murine Progenitor Cell Expansion and Preserves Stem Cell Function

Inflammation causes increased signaling and proliferation in hematopoietic stem and progenitor cells (HSPCs), but the specific role of anti-inflammatory cytokines such as IL-10 on HSPCs is less clear. Using IL-10 receptor (IL-10R)-deficient mice we observed an increased frequency and number of HSPCs in the bone marrow (BM) relative to wild-type (WT) mice with an increased frequency of mature myeloid cells. Consistent with this, we observed reduced expansion of WT lineage-negative HSPCs after in vitro exposure to IL-10 with a specifically pronounced suppression of MPP2 cells. This reduced expansion was not observed with IL-22 or IFN-?2, cytokines which signal through receptors that also contain the IL-10 receptor common ß chain or with HSPCs from Il10ra-/- mice. To understand the mechanism of reduced expansion of MPP2 cells and preserved HSC numbers in mice with intact IL-10 signaling, we stimulated FACS-purified WT cells with IL-10 and performed expression analysis. IL-10 stimulation of HSCs increased the non-canonical Wnt pathway gene Wnt4 which is implicated in HSC quiescence and long-term function. In contrast, IL-10 stimulation in MPP2 cells modulated the TGFß pathway and increased the expression of E2f5, a transcription factor that negatively regulates proliferation. Taken together, this study reveals a previously unrecognized role for IL-10 in suppressing HSPC cell expansion and promoting HSC function. Overall design: mRNA profiles of MPP2 and LT-HSC cells after stimulation with IL-10