Cell-extrinsic signals drive altered HSC function in miR-146a^−/−mice. (A) A gene expression network upregulated in miR-146a^−/− vs WT HSPCs shows overlap between GO terms involved in cell proliferation and differentiation (yellow) and those involved in immunity and cytokine production. EnrichmentMap cutoffs: FDR <0.075; P < .005; and overlap >.75. AutoAnnotate network labels: community cluster analysis of GO term names. (B) Cotransplantation experiment assessing the cell nonautonomous effect of miR-146a^−/− BM on HSC function. WT_Ly5.1 BM was cotransplanted with WT or miR-146a^−/−_Ly5.2 BM in Ly5.1/5.2 hybrid recipients, followed by 2° LDA transplants. Dashed box represents the WT cells of interest assessed in panels C-D. (C) Extreme limiting dilution analysis (ELDA) plot for secondary transplants with WT_Ly5.1 that had been cotransplanted with WTL_y5.2 (WT in WT+WT) vs miR-146a^−/−_Ly5.2 (WT in WT+ −/−) BM (n = 36 mice per genotype, with 7 dilutions). (D) Number of serially transplantable WT_Ly5.1 HSCs estimated from ELDA analysis shown in panel C. P by ELDA.