Pharmacologic PPAR-γ activation reprograms bone marrow macrophages and partially rescues HSPC mobilization in human and murine diabetes

Mobilization of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow (BM) is impaired in diabetes. Excess oncostatin M (OSM) produced by M1 macrophages in the diabetic BM signals through p66Shc to induce <i>Cxcl12</i> in stromal cells and retain HSPCs. BM adipocytes are another source of CXCL12 that blunts mobilization. We tested a strategy of pharmacologic macrophage reprogramming to rescue HSPC mobilization. <i>In vitro</i>, PPAR-γ activation with pioglitazone switched macrophages from M1 to M2, reduced <i>Osm</i> expression, and prevented transcellular induction of <i>Cxcl12</i>. In diabetic mice,<i> </i>pioglitazone treatment downregulated <i>Osm</i>, <i>p66Shc</i> and <i>Cxcl12</i> in the hematopoietic BM, restored the effects of granulocyte-colony stimulation factor (G-CSF), and partially rescued HSPC mobilization, but it increased BM adipocytes. <i>Osm</i> deletion recapitulated the effects of pioglitazone on adipogenesis, which was p66Shc-independent, and double knockout of Osm and p66Shc completely rescued HSPC mobilization<i>. </i>In the absence of OSM, BM adipocytes produced less CXCL12, being arguably devoid of HSPC-retaining activity, whereas pioglitazone failed to downregulate <i>Cxcl12</i> in BM adipocytes. In diabetic patients under pioglitazone therapy, HSPC mobilization after G-CSF was partially rescued. In summary, pioglitazone reprogrammed BM macrophages and suppressed OSM signaling, but sustained <i>Cxcl12</i> expression by BM adipocytes could limit full recovery of HSPC mobilization.