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Pharmacologic PPAR-γ Activation Reprograms Bone Marrow Macrophages and Partially Rescues HSPC Mobilization in Human
Serena Tedesco1,2, Stefano Ciciliot1, Lisa Menegazzo1
1Veneto Institute of Molecular Medicine, Padova, Italy.
Abstract:
Mobilization of hematopoietic stem/progenitor cells (HSPC) 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 HSPC. 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 patients with diabetes on 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.
Insights
Pioglitazone partially rescues hematopoietic stem cell mobilization in diabetes by reprogramming macrophages and reducing Oncostatin M (OSM) signaling. However, sustained CXCL12 from bone marrow adipocytes limits full recovery.
Area of Science:
- Hematology
- Immunology
- Endocrinology
Background:
- Hematopoietic stem/progenitor cell (HSPC) mobilization from bone marrow (BM) is impaired in diabetes.
- Excess Oncostatin M (OSM) from M1 macrophages in diabetic BM induces CXCL12 in stromal cells, retaining HSPC.
- Bone marrow adipocytes also contribute to CXCL12 production, further hindering mobilization.
Purpose of the Study:
- To investigate pharmacologic macrophage reprogramming using pioglitazone to restore HSPC mobilization in diabetes.
- To elucidate the roles of OSM, p66Shc, and CXCL12 in diabetic BM and their modulation by pioglitazone.
Main Methods:
- In vitro studies on macrophage polarization and gene expression.
- In vivo experiments in diabetic mice treated with pioglitazone or subjected to gene deletion (Osm, p66Shc).
- Analysis of HSPC mobilization, gene expression (Osm, p66Shc, Cxcl12), and bone marrow adipogenesis.
- Clinical evaluation in diabetic patients receiving pioglitazone and G-CSF therapy.
Main Results:
- Pioglitazone switched M1 to M2 macrophages in vitro, reducing Osm and preventing CXCL12 induction.
- In diabetic mice, pioglitazone downregulated Osm, p66Shc, and Cxcl12, partially rescuing HSPC mobilization but increasing BM adipocytes.
- Osm deletion mimicked pioglitazone's effects on adipogenesis independently of p66Shc.
- Combined Osm and p66Shc knockout completely rescued HSPC mobilization.
- In patients, pioglitazone partially rescued G-CSF-induced HSPC mobilization.
Conclusions:
- Pioglitazone reprograms bone marrow macrophages, suppressing OSM signaling and partially rescuing HSPC mobilization.
- Sustained CXCL12 expression by bone marrow adipocytes limits the complete recovery of HSPC mobilization.
- Targeting both macrophage-derived OSM and adipocyte-derived CXCL12 may be necessary for full restoration of HSPC mobilization in diabetes.
