Diabetes Impairs Stem Cell and Proangiogenic Cell Mobilization in Humans

Fadini, Gian Paolo; Albiero, Mattia; Kreutzenberg, Saula Vigili de; Boscaro, Elisa; Cappellari, Roberta; Marescotti, Mariacristina; Poncina, Nicol; Agostini, Carlo; Avogaro, Angelo

doi:10.2337/dc12-1084

Cited by 168 publications

(173 citation statements)

References 28 publications

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“…In turn, microangiopathy causes BM dysfunction and alters stem cell regulation [23]. Thus, we analyzed monocyte subsets in BM aspirates of type 2 diabetic and control patients.…”

Section: Discussionmentioning

confidence: 99%

An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy

et al. 2013

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AIM/HYPOTHESIS: Monocytes/macrophages play important roles in adipose and vascular tissues and can be polarised as inflammatory M1 or anti-inflammatory M2. We sought to analyse monocyte polarisation status in type 2 diabetes, which is characterised by chronic inflammation. METH-ODS: We enrolled 60 individuals without diabetes and 53 patients with type 2 diabetes. We quantified standard monocyte subsets defined by cluster of differentiation (CD)14 and CD16. In addition, based on the phenotype of polarised macrophages in vitro, we characterised and quantified more definite M1 (CD68(+)CCR2(+)) and M2 (CX3CR1(+)CD206(+)/CD163(+)) monocytes. We also analysed bone marrow (BM) samples and the effects of granulocyte-colony stimulating factor (G-CSF) stimulation in diabetic and control individuals. RESULTS: We found no alterations in standard monocyte subsets (classical, intermediate and non-classical) when comparing groups. For validation of M1 and M2 phenotypes, we observed that M2 were enriched in non-classical monocytes and had lower TNF-content, higher LDL scavenging and lower transendothelial migratory capacity than M1. Diabetic patients displayed an imbalanced M1/M2 ratio compared with the control group, attributable to a reduction in M2. The M1/M2 ratio was directly correlated with waist circumference and HbA1c and, among diabetic patients, M2 reduction and M1/M2 increase were associated with microangiopathy. A decrease in M2 was also found in the BM from diabetic patients, with a relative M2 excess compared with the bloodstream. BM stimulation with G-CSF mobilised M2 macrophages in diabetic but not in healthy individuals. CON-CLUSIONS/INTERPRETATION: We show that type 2 diabetes markedly reduces anti-inflammatory M2 monocytes through a dysregulation in bone-marrow function. This defect may have a negative impact on microangiopathy. DOI: https://doi.org/10.1007/s00125-013-2918-9Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-83908 Accepted Version Originally published at: Fadini, G P; de Kreutzenberg, S Vigili; Boscaro, E; Albiero, M; Cappellari, R; Kränkel, N; Landmesser, U; Toniolo, A; Bolego, C; Cignarella, A; Seeger, F; Dimmeler, S; Zeiher, A; Agostini, C; Avogaro, A (2013). An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy. Diabetologia, 56 (8) (CX3CR1+CD206+/CD163+) monocytes. We also analysed bone marrow (BM) samples and the effects of G-CSF stimulation in type 2 diabetic and control subjects.Results. We found no alterations in standard monocyte subsets (classical, intermediate, and nonclassical) between groups. For validation of M1 and M2 phenotypes, we show that M2 were enriched in nonclassical monocytes, had lower TNF-α content, higher LDL scavenging and lower transendothelial migratory capacity than M1. Diabetic patients displayed an imbalanced M1/M2 ratio compared to controls, which was attributable to a reduction in M2. The M1/M2 ratio was d...

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“…In turn, microangiopathy causes BM dysfunction and alters stem cell regulation [23]. Thus, we analyzed monocyte subsets in BM aspirates of type 2 diabetic and control patients.…”

Section: Discussionmentioning

confidence: 99%

An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy

et al. 2013

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“…Human circulating monocyte-macrophages were identified and quantified as previously described (21 + SCs were quantified as previously described (9). We used the protocol described by Chow et al (19) …”

Section: Facs Analysismentioning

confidence: 99%

“…Details on inclusion and exclusion criteria and clinical characterization of patients are provided in the Supplementary Data. Enrollment in the BM stimulation protocol and treatment with G-CSF in the trial NCT01102699 are described elsewhere (9). Coupled peripheral blood (PB) and BM samples were collected from patients undergoing hip replacement surgery.…”

Section: Patientsmentioning

confidence: 99%

“…Extensive remodeling of the BM microvasculature has been demonstrated in mice (3) and patients (4) with diabetes. Along with autonomic neuropathy (5), such profound alterations in the stem cell (SC) niche cause BM dysfunction, evidenced by an impaired SC mobilization in response to ischemia (6,7) and granulocyte-colony stimulation factor (G-CSF) (8,9). This novel type of chronic diabetes complication, termed "stem cell mobilopathy" (10), has implications for the care of patients with diabetes with hematological disorders.…”

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confidence: 99%

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Bone Marrow Macrophages Contribute to Diabetic Stem Cell Mobilopathy by Producing Oncostatin M

et al. 2015

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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 (BMMF) prevent SC mobilization, we hypothesized that excess BMMF contribute to diabetic SC mobilopathy. We show that patients with diabetes have increased M1 macrophages, whereas diabetic mice have increased CD169+ BMMF with SC-retaining activity. Depletion of BMMF 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 mitogenactivated 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, BMMF 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.

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“…A reduced response to G-CSF-induced mobilisation in type 1 and type 2 diabetes models has been confirmed in mice [113]. Diabetic patients are also unresponsive to the effects of G-CSF, which fails to mobilise CD34 + cells and EPCs [114,115]. This is likely to be due to the profound remodelling induced by diabetes in the BM microenvironment.…”

Section: The Bm In Diabetesmentioning

confidence: 96%

A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications

Fadini

2013

Diabetologia

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Traditionally, the development of diabetic complications has been attributed to the biochemical pathways driving hyperglycaemic cell damage, while reparatory mechanisms have been long overlooked. A more comprehensive view of the balance between damage and repair suggests that an impaired regenerative capacity of bone marrow (BM)-derived cells strongly contributes to defective re-endothelisation and neoangiogenesis in diabetes. Although recent technological advances have redefined the biology and function of endothelial progenitor cells (EPCs), interest in BM-derived vasculotropic cells in the setting of diabetes and its complications remains high. Several circulating cell types of haematopoietic and non-haematopoietic origin are affected by diabetes and are potentially involved in the pathobiology of chronic complications. In addition to classical EPCs, these include circulating (pro-)angiogenic cells, polarised monocytes/macrophages (M1 and M2), myeloid calcifying cells and smooth muscle progenitor cells, having disparate roles in vascular biology. In parallel with the study of elusive progenitor cell phenotypes, it has been recognised that diabetes induces a profound remodelling of the BM stem cell niche. The alteration of circulating (progenitor) cells in the BM is now believed to be the link among distant end-organ complications. The field is rapidly evolving and interest is shifting from specific cell populations to the complex network of interactions that orchestrate trafficking of circulating vasculotropic cells.

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Diabetes Impairs Stem Cell and Proangiogenic Cell Mobilization in Humans

Cited by 168 publications

References 28 publications

An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy

An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy

Bone Marrow Macrophages Contribute to Diabetic Stem Cell Mobilopathy by Producing Oncostatin M

A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications

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