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- Title
Diabetes-Associated Myelopoiesis Drives Stem Cell Mobilopathy Through an OSM-p66Shc Signaling Pathway.
- Authors
Albiero, Mattia; Ciciliot, Stefano; Tedesco, Serena; Menegazzo, Lisa; D’Anna, Marianna; Scattolini, Valentina; Cappellari, Roberta; Zuccolotto, Gaia; Rosato, Antonio; Cignarella, Andrea; Giorgio, Marco; Avogaro, Angelo; Fadini, Gian Paolo
- Abstract
Diabetes impairs the mobilization of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow (BM), which can worsen the outcomes of HSPC transplantation and of diabetic complications. In this study, we examined the oncostatin M (OSM)–p66Shc pathway as a mechanistic link between HSPC mobilopathy and excessive myelopoiesis. We found that streptozotocininduced diabetes in mice skewed hematopoiesis toward the myeloid lineage via hematopoietic-intrinsic p66Shc. The overexpression of Osm resulting from myelopoiesis prevented HSPC mobilization after granulocyte colonystimulating factor (G-CSF) stimulation. The intimate link between myelopoiesis and impaired HSPC mobilization after G-CSF stimulation was confirmed in human diabetes. Using cross-transplantation experiments, we found that deletion of p66Shc in the hematopoietic or nonhematopoietic system partially rescued defective HSPC mobilization in diabetes. Additionally, p66Shc mediated the diabetes-inducedBMmicrovasculature remodeling. Ubiquitous or hematopoietic restrictedOsmdeletion phenocopied p66Shc deletion in preventing diabetesassociated myelopoiesis and mobilopathy. Mechanistically, we discovered that OSM couples myelopoiesis to mobilopathy by inducing Cxcl12 in BM stromal cells via nonmitochondrial p66Shc. Altogether, these data indicate that cell-autonomous activation of the OSM-p66Shc pathway leads to diabetes-associated myelopoiesis, whereas its transcellular hematostromal activation links myelopoiesis to mobilopathy. Targeting the OSM-p66Shc pathway is a novel strategy to disconnect mobilopathy from myelopoiesis and restore normal HSPC mobilization.
- Subjects
STEM cells; HEMATOPOIETIC system; KIDNEY transplant complications; PROGENITOR cells; BONE marrow
- Publication
Diabetes, 2019, Vol 68, Issue 6, p1303
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db19-0080