Diabetes-associated myelopoiesis drives stem cell mobilopathy through an OSM-p66Shc signaling pathway

Mattia Albiero, Stefano Ciciliot, Serena Tedesco, Lisa Menegazzo, Marianna D’Anna, Valentina Scattolini, Roberta Cappellari, Gaia Zuccolotto, Antonio Rosato, Andrea Cignarella, Marco Giorgio, Angelo Avogaro, Gian Paolo Fadini

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)1303-1314
Number of pages12
JournalDiabetes
Volume68
Issue number6
DOIs
Publication statusPublished - Jun 1 2019

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Albiero, M., Ciciliot, S., Tedesco, S., Menegazzo, L., D’Anna, M., Scattolini, V., Cappellari, R., Zuccolotto, G., Rosato, A., Cignarella, A., Giorgio, M., Avogaro, A., & Fadini, G. P. (2019). Diabetes-associated myelopoiesis drives stem cell mobilopathy through an OSM-p66Shc signaling pathway. Diabetes, 68(6), 1303-1314. https://doi.org/10.2337/db19-0080