PT  - JOURNAL ARTICLE
AU  - Albiero, Mattia
AU  - Ciciliot, Stefano
AU  - Tedesco, Serena
AU  - Menegazzo, Lisa
AU  - D’Anna, Marianna
AU  - Scattolini, Valentina
AU  - Cappellari, Roberta
AU  - Zuccolotto, Gaia
AU  - Rosato, Antonio
AU  - Cignarella, Andrea
AU  - Giorgio, Marco
AU  - Avogaro, Angelo
AU  - Fadini, Gian Paolo
TI  - Diabetes-Associated Myelopoiesis Drives Stem Cell Mobilopathy Through an OSM-p66Shc Signaling Pathway
AID  - 10.2337/db19-0080
DP  - 2019 Jun 01
TA  - Diabetes
PG  - 1303--1314
VI  - 68
IP  - 6
4099  - http://diabetes.diabetesjournals.org/content/68/6/1303.short
4100  - http://diabetes.diabetesjournals.org/content/68/6/1303.full
SO  - Diabetes2019 Jun 01; 68
AB  - 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 streptozotocin-induced 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 colony-stimulating 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-induced BM microvasculature remodeling. Ubiquitous or hematopoietic restricted Osm deletion phenocopied p66Shc deletion in preventing diabetes-associated 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.