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

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posted on 28.04.2020 by Ada Admin, Serena Tedesco, Stefano Ciciliot, Lisa Menegazzo, Marianna D’Anna, Valentina Scattolini, Roberta Cappellari, Andrea Cignarella, Angelo Avogaro, Mattia Albiero, Gian Paolo Fadini
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 Cxcl12 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. In vitro, PPAR-γ activation with pioglitazone switched macrophages from M1 to M2, reduced Osm expression, and prevented transcellular induction of Cxcl12. In diabetic mice, pioglitazone treatment downregulated Osm, p66Shc and Cxcl12 in the hematopoietic BM, restored the effects of granulocyte-colony stimulation factor (G-CSF), and partially rescued HSPC mobilization, but it increased BM adipocytes. Osm deletion recapitulated the effects of pioglitazone on adipogenesis, which was p66Shc-independent, and double knockout of Osm and p66Shc completely rescued HSPC mobilization. In the absence of OSM, BM adipocytes produced less CXCL12, being arguably devoid of HSPC-retaining activity, whereas pioglitazone failed to downregulate Cxcl12 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 Cxcl12 expression by BM adipocytes could limit full recovery of HSPC mobilization.

Funding

The study was supported by the following grants: European Foundation for the Study of Diabetes (EFSD)/Novartis 2013 grant to GPF; EFSD/Lilly 2016 grant to GPF; Ministry of University and Education PRIN grant 2015 to GPF; Italian Diabetes Society/Lilly grant 2017 to GPF.

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