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

Fadini, Gian Paolo

doi:10.1007/s00125-013-3087-6

Cited by 65 publications

(67 citation statements)

References 126 publications

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“…Identification of OSM as the mediator of macrophage-retaining activity has therapeutic implications to revert diabetic SC mobilopathy and, potentially, in other "poor mobilizer" conditions. Because BM-derived cells play a major role in diabetes complications (36), restoration of BMSC mobilization with a targeted molecular approach may restore endogenous vascular regenerative capacity and improve the outcome of patients with diabetes. …”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…Nowadays, shortage of EPCs is considered a contributor to the development of diabetes complications. Therefore, investigations into the mechanisms that impair EPC in diabetes are of great interest to devise new endogenous regenerative therapeutic strategies (115). Experimental modeling suggests that the low circulating EPC level in diabetes is attributable to impaired mobilization from the BM.…”

Section: Dpp4-i and The Diabetic Bmmentioning

confidence: 99%

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

2014

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We performed a review of the literature to determine whether the dipeptidyl peptidase-4 inhibitors (DPP4-I) may have the capability to directly and positively influence diabetic microvascular complications. The literature was scanned to identify experimental and clinical evidence that DPP4-I can ameliorate diabetic microangiopathy. We retrieved articles published between 1 January 1980 and 1 March 2014 in English-language peer-reviewed journals using the following terms: (“diabetes” OR “diabetic”) AND (“retinopathy” OR “retinal” OR “nephropathy” OR “renal” OR “albuminuria” OR “microalbuminuria” OR “neuropathy” OR “ulcer” OR “wound” OR “bone marrow”); (“dipeptidyl peptidase-4” OR “dipeptidyl peptidase-IV” OR “DPP-4” OR “DPP-IV”); and (“inhibition” OR “inhibitor”). Experimentally, DPP4-I appears to improve inflammation, endothelial function, blood pressure, lipid metabolism, and bone marrow function. Several experimental studies report direct potential beneficial effects of DPP4-I on all microvascular diabetes-related complications. These drugs have the ability to act either directly or indirectly via improved glucose control, GLP-1 bioavailability, and modifying nonincretin substrates. Although preliminary clinical data support that DPP4-I therapy can protect from microangiopathy, insufficient evidence is available to conclude that this class of drugs directly prevents or decreases microangiopathy in humans independently from improved glucose control. Experimental findings and preliminary clinical data suggest that DPP4-I, in addition to improving metabolic control, have the potential to interfere with the onset and progression of diabetic microangiopathy. Further evidence is needed to confirm these effects in patients with diabetes.

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“…[49][50][51][52][53] Although these abnormalities might not cause a major defect in hematopoiesis, they are associated with reduced differentiation and release of EPCs. Experimental 50,51 and human studies 54,55 also demonstrate that DM impairs the mobilization of EPCs in response to tissue ischemia or cytokines, such as granulocyte colony-stimulating factor. Among the several different mechanisms, eNOS dysfunction 56 and altered cytokine gradients, for example, stromal-derived factor 1α (SDF-1α) between the BM and ischemic tissues in DM, 50,55 may play major roles in the impairment of EPC mobilization.…”

Section: Differentiation and Mobilizationmentioning

confidence: 99%

Specific Role of Impaired Glucose Metabolism and Diabetes Mellitus in Endothelial Progenitor Cell Characteristics and Function

Yiu

Tse

2014

ATVB

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Abstract-The disease burden of diabetes mellitus (DM) and its associated cardiovascular complications represent a growing and major global health problem. Recent studies suggest that circulating exogenous endothelial progenitor cells (EPCs) play an important role in endothelial repair and neovascularization at sites of injury or ischemia. 1 This has been attributed to the occurrence of endothelial dysfunction that leads to the initiation and progression of atherosclerotic vascular disease 2 and impaired neovascularization after ischemia induced by hyperglycemia. 3,4 In patients with impaired glucose metabolism and DM, the vascular endothelium is challenged by inflammation, reactive oxygen species, and deletion of endothelial nitric oxide synthase (eNOS) with resultant endothelial dysfunction.2,5-7 The depletion and dysfunction of the circulating endothelial progenitor cells (EPCs) are thought to underlie the endothelial dysfunction in DM. In this review, the possible mechanisms, functional consequences, and the potential therapeutic approach for impaired EPCs in DM are discussed. A systematic literature search for full-text papers in the English language was performed using MEDLINE, Embase, and the Cochrane library through to February 2014. In the search phrases used, the following terms were combined with the phrase AND Diabetes: endothelial progenitor cells, cardiovascular disease, myocardial infarction, and stroke.

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

Cited by 65 publications

References 126 publications

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

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

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

Specific Role of Impaired Glucose Metabolism and Diabetes Mellitus in Endothelial Progenitor Cell Characteristics and Function

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