title: Bone Marrow Macrophages Contribute to Diabetic Stem Cell Mobilopathy by Producing Oncostatin M.
abstract: Diabetes affects bone marrow (BM) structure and impairs mobilization of stem cells (SCs) into peripheral blood (PB). This amplifies multiorgan complications because BMSCs promote vascular repair. Because diabetes skews macrophage phenotypes and BM macrophages (BMMΦ) prevent SC mobilization, we hypothesized that excess BMMΦ contribute to diabetic SC mobilopathy. We show that patients with diabetes have increased M1 macrophages, whereas diabetic mice have increased CD169(+) BMMΦ with SC-retaining activity. Depletion of BMMΦ restored SC mobilization in diabetic mice. We found that CD169 labels M1 macrophages and that conditioned medium (CM) from M1 macrophages, but not from M0 and M2 macrophages, induced chemokine (C-X-C motif) ligand 12 (CXCL12) expression by mesenchymal stem/stromal cells. In silico data mining and in vitro validation identified oncostatin M (OSM) as the soluble mediator contained in M1 CM that induces CXCL12 expression via a mitogen-activated protein kinase kinase-p38-signal transducer and activator of a transcription 3-dependent pathway. In diabetic mice, OSM neutralization prevented CXCL12 induction and improved granulocyte-colony stimulating factor and ischemia-induced mobilization, SC homing to ischemic muscles, and vascular recovery. In patients with diabetes, BM plasma OSM levels were higher and correlated with the BM-to-PB SC ratio. In conclusion, BMMΦ prevent SC mobilization by OSM secretion, and OSM antagonism is a strategy to restore BM function in diabetes, which can translate into protection mediated by BMSCs.
authors: Department of Medicine, University of Padova, Padova, Italy Venetian Institute of Molecular Medicine, Padova, Italy.
authors: Mattia
authors: M
authors: Albiero
authors: Department of Medicine, University of Padova, Padova, Italy Venetian Institute of Molecular Medicine, Padova, Italy.
authors: Nicol
authors: N
authors: Poncina
authors: Department of Medicine, University of Padova, Padova, Italy Venetian Institute of Molecular Medicine, Padova, Italy.
authors: Stefano
authors: S
authors: Ciciliot
authors: Department of Medicine, University of Padova, Padova, Italy.
authors: Roberta
authors: R
authors: Cappellari
authors: Department of Medicine, University of Padova, Padova, Italy Venetian Institute of Molecular Medicine, Padova, Italy.
authors: Lisa
authors: L
authors: Menegazzo
authors: Pennsylvania Hospital, University of Pennsylvania Health System, Philadelphia, PA Fox Chase Cancer Center, Philadelphia, PA.
authors: Francesca
authors: F
authors: Ferraro
authors: Department of Pharmaceutical Sciences, University of Padova, Italy.
authors: Chiara
authors: C
authors: Bolego
authors: Department of Medicine, University of Padova, Padova, Italy.
authors: Andrea
authors: A
authors: Cignarella
authors: Department of Medicine, University of Padova, Padova, Italy Venetian Institute of Molecular Medicine, Padova, Italy.
authors: Angelo
authors: A
authors: Avogaro
authors: Department of Medicine, University of Padova, Padova, Italy Venetian Institute of Molecular Medicine, Padova, Italy gianpaolofadini@hotmail.com gianpaolo.fadini@unipd.it.
authors: Gian Paolo
authors: GP
authors: Fadini
mesh_terms: D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D053683:Oncostatin M / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D053683:Oncostatin M