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Diabetes-Associated Myelopoiesis Drives Stem Cell Mobilopathy Through an OSM-P66shc Signaling Pathway

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Diabetes-Associated Myelopoiesis Drives Stem Cell Mobilopathy Through an OSM-P66shc Signaling Pathway Page 1 of 40 Diabetes 1 Diabetes-associated myelopoiesis drives stem cell mobilopathy through an OSM-p66Shc signaling pathway Mattia Albiero1,2*, Stefano Ciciliot1*, Serena Tedesco1,2, Lisa Menegazzo1, Marianna D’Anna1,2, Valentina Scattolini1,2, Roberta Cappellari1,2, Gaia Zuccolotto3,4, Antonio Rosato3,4, Andrea Cignarella2, Marco Giorgio5,6, Angelo Avogaro2, and Gian Paolo Fadini1,2 * The first two authors contributed equally 1 Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy 2 Department of Medicine – DIMED, University of Padova, 35128 Padova, Italy 3 Department of Surgery, Oncology and Gastroenterology, University of Padova, 35129 Padova, Italy 4 Istituto Oncologico Veneto IOV-IRCCS, 35128 Padova, Italy 5 European Institute of Oncology (IEO), 20139 Milan, Italy 6 Department of Biomedical Sciences, 35131 Padova, Italy Corresponding author Gian Paolo Fadini Associate Professor of Endocrinology Department of Medicine, University of Padova Via Giustiniani 2, 35128 Padova, Italy Phone +39 049 8214318 Fax: +39 049 8212184 Email: [email protected] [email protected] Running title: OSM-p66Shc regulates mobilopathy/myelopoiesis Diabetes Publish Ahead of Print, published online April 1, 2019 Diabetes Page 2 of 40 2 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 (STZ)-induced diabetes in mice skewed hematopoiesis towards the myeloid lineage, via hematopoietic-intrinsic p66Shc. The overexpression of Osm resulting from myelopoiesis prevented HSPC mobilization after G-CSF. The intimate link between myelopoiesis and impaired HSPC mobilization after G-CSF was confirmed in human diabetes. Using cross-transplantation experiments, we found that deletion of p66Shc in the hematopoietic or non-hematopoietic 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 non-mitochondrial p66Shc. Altogether, these data indicate that cell-autonomous activation of the OSM-p66Shc pathway leads to diabetes-associated myelopoiesis, whereas its transcellular hemato-stromal activation links myelopoiesis to mobilopathy. Targeting the OSM-p66Shc pathway is a novel strategy to disconnect mobilopathy from myelopoiesis and restore normal HSPC mobilization. Page 3 of 40 Diabetes 3 Diabetes is associated with low-grade inflammation, which contributes to chronic complications (1; 2). A skewed differentiation of common myeloid progenitors (CMP) translates hyperglycemia into production of pro-inflammatory cells (3). Such enhanced myelopoiesis propagates inflammation from the bone marrow (BM) to the adipose and the vasculature, leading to insulin resistance and atherosclerosis (3; 4). In parallel, mobilization of hematopoietic stem/progenitor cells (HSPCs) from the BM to peripheral blood (PB) after stimulation with granulocyte colony stimulation factor (G-CSF) is impaired in murine (5; 6) and human diabetes (7; 8), a condition termed mobilopathy (9). We herein hypothesize that myelopoesis and mobilopathy, described as two distinct pathological features of the diabetic BM, are instead mechanistically linked. Disentangling the processes linking myelopoiesis to mobilopathy has relevant clinical implications. First, pharmacologic mobilization of HSPCs is the gold standard for HSPC transplantation (10) and failure to collect robust numbers of HSPCs can delay engraftment, thereby worsening the outcome of diabetic patients undergoing transplantation (5). Second, reduction of circulating HSPCs in diabetic patients predicts the future development of micro- and macrovascular complications (11; 12). Glucose control effectively prevents myelopoiesis and partially rescues HSPC mobilization (3; 13), but many patients fail to achieve necessary glucose targets. Therefore, disconnecting mobilopathy from myelopoiesis can provide a direct therapeutic strategy to restore normal HSPC mobilization. Recent studies highlight that murine and human diabetes cause BM microvascular remodeling (14) and autonomic neuropathy (6; 15), both of which can affect HSPC traffic (16; 17). We previously found that BM denervation in diabetic mice accounts for impaired response to G-CSF and is mediated by p66Shc (6). Unlike p46 and p52, p66Shc functions both as an adaptor protein for membrane receptors and a redox enzyme. Upon phosphorylation at Ser36, p66Shc translocates to the mitochondrial intermembrane space where it catalyzes the production of hydrogen peroxide (18), contributing to processes linked to oxidative stress, including diabetic complications (19; 20). Besides sympathetic nervous system (SNS) activation, depletion of BM macrophages is a key event in the mobilization cascade induced by G-CSF, because macrophage paracrine activity sustains CXCL12 production (21). We have identified oncostatin M (OSM) as the macrophage-derived soluble factor that induces Cxcl12 expression in stromal cells, thereby antagonizing HSPC mobilization (22). OSM is a cytokine of the IL-6 family, which signals via MAP kinase and the JAK/STAT pathways, leading to pleiotropic functions including modulation of inflammation and bone formation (23; 24). In murine diabetes, excess BM macrophages result in persistent OSM signaling, inability to switch off CXCL12 levels after G-CSF, and impaired HSPC mobilization (22). Thus, OSM represents a candidate link between myelopoiesis and mobilopathy. In view of the similar benefits of p66Shc deletion and OSM inhibition on the diabetic stem cell mobilopathy (6; 22), we have hypothesized that the two pathways are mechanistically connected. In the current study, we therefore examined the interplay between OSM and p66Shc in determining the link between myelopoiesis and mobilopathy observed in experimental and human diabetes. RESEARCH DESIGN AND METHODS Diabetes Page 4 of 40 4 Mice C57BL/6J wild type mice were purchased from Jackson Laboratories and established as a colony since 2001. p66Shc-/- mice were originally obtained from Pelicci’s laboratory (European Institute of Oncology, Milan, Italy), a colony was established at our facility in 2010, and mice have been backcrossed on the C57BL/6J background for >10 generations. Osm-/- mice on the C57BL/6J background were obtained from Glaxo Smith Kline (GSK, Stevenage, UK) and a colony was established since 2015. For all the experiments, we used sex- and age-matched animals. Assignment of mice to treatments or experimental groups was based on a computer generated random sequence. All animal studies were approved by the Animal Care and Use Committee of Venetian Institute of Molecular Medicine and by the Italian Health Ministry. Humans Diabetic and non-diabetic individuals were recruited at the Division of Metabolic Diseases of the University Hospital of Padova. The protocols were approved by the local ethical committee and conducted in accordance with the Declaration of Helsinki as revised in 2000. Cross-sectional data on the association between myeloid bias and circulating HSPCs were derived from two previous studies that had been approved by the local ethics committee (6; 25). Total and differential white blood cell (WBC) count were determined in the same laboratory for both studies and CD34+ HSPC levels were quantified by flow cytometry relative to WBC. Details are given the in previous publications (6; 25). The study for G-CSF-induced mobilization was approved by the local ethics committee and is registered in ClinicalTrials.gov (NCT01102699). This was a prospective, parallel group study of direct BM stimulation with G-CSF in subjects with and without diabetes. Specific methods for quantifying blood cells and HSPCs were given in the previous publication (7). Informed consent was obtained from all participants. Animal models Diabetes was induced in 2 months-old mice by a single intraperitoneal injection of 175 mg/kg streptozotocin (STZ). Blood glucose was measured using a FreeStyle glucometer (Abbott, IL, USA). HSPC mobilization was induced by s.c. injection of 200 g/kg/die G-CSF daily for 4 days. 3 months-old mice where treated with vehicle or carrier free recombinant mouse Oncostatin-M (495-MO/CF, R&D Systems, MN, USA) at 0.5 ug per injection every 6 hours for 48 hours before performing analysis. Total WBC count was performed using the CELL-DYN Emerald hematology analyzer (Abbott, IL, USA) on fresh EDTA-treated mouse blood. MEF transduction MEFs were isolated from E13.5 p66Shc-/- mice after digestion with trypsin (Corning) and cultured with DMEM, 10% FBS. PINCO retroviral particles were produced from the amphotropic packaging cell line Phoenix. Cells were infected either with an empty vector, a vector encoding mouse full-length p66Shc, a vector encoding the mutants p66ShcS36A (S→A substitution at position 36) and p66ShcQQ (EE→QQ substitutions Page 5 of 40 Diabetes 5 at positions 132-133). P3 MEFs were infected with 3 rounds of infection with Polybrene Infection / Transfection Reagent (Sigma-Aldrich) followed by 96 hours of selection
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