Diabetes mellitus as a poor mobilizer condition

Fadini, Gian Paolo; DiPersio, John F.

doi:10.1016/j.blre.2017.11.002

Cited by 26 publications

(13 citation statements)

References 85 publications

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“…Countering the mechanisms driving chronic shortage of circulating HSPC is expected to improve micro-and macrovascular outcomes (7). Enhancing HSPC mobilization in patients with diabetes could also improve the outcome of autologous transplantation for the treatment of blood cancer (1). We show that PPAR-g is a new candidate target to rescue the impaired HSPC mobilization consistently observed in human and experimental diabetes.…”

Section: Discussionmentioning

confidence: 75%

“…CXCL12 is the major regulator of HSPC traffic in and out the BM: high levels of CXCL12 keep HSPC in their niches (12), whereas mobilizing stimuli act by reducing intramarrow CXCL12 concentrations (like G-CSF [13]) by desensitizing cells to CXCL12 (like plerixafor [14]) or by inverting the gradient of CXCL12 from the BM to PB (dipeptidyl peptidase 4 [DPP4] inhibitors [15]). The observation that DPP-4 inhibitors and plerixafor mobilize HSPC in diabetes (7) supports the concept that an ineffective CXCL12 switch causes diabetes-associated G-CSF unresponsiveness (1). In addition, the BM of diabetic rodents and patients with diabetes undergoes extensive remodeling, including adipocyte accumulation (8,16,17).…”

mentioning

confidence: 64%

“…Studies performed in experimental and human diabetes have consistently shown an impaired mobilization of hematopoietic stem/progenitor cells (HSPC) from the bone marrow (BM) to peripheral blood (PB) after stimulation with granulocytecolony stimulation factor (G-CSF) (1). Such mobilization defect precedes the reduction of circulating HSPC (2,3), which, in turn, is a driver of micro-and macrovascular complications (4,5).…”

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confidence: 99%

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Pharmacologic PPAR-γ Activation Reprograms Bone Marrow Macrophages and Partially Rescues HSPC Mobilization in Human and Murine Diabetes

et al. 2020

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Mobilization of hematopoietic stem/progenitor cells (HSPC) from the bone marrow (BM) is impaired in diabetes. Excess oncostatin M (OSM) produced by M1 macrophages in the diabetic BM signals through p66Shc to induce Cxcl12 in stromal cells and retain HSPC. BM adipocytes are another source of CXCL12 that blunts mobilization. We tested a strategy of pharmacologic macrophage reprogramming to rescue HSPC mobilization. In vitro, PPAR-g activation with pioglitazone switched macrophages from M1 to M2, reduced Osm expression, and prevented transcellular induction of Cxcl12. In diabetic mice, pioglitazone treatment downregulated Osm, p66Shc, and Cxcl12 in the hematopoietic BM, restored the effects of granulocytecolony stimulation factor (G-CSF), and partially rescued HSPC mobilization, but it increased BM adipocytes. Osm deletion recapitulated the effects of pioglitazone on adipogenesis, which was p66Shc independent, and double knockout of Osm and p66Shc completely rescued HSPC mobilization. In the absence of OSM, BM adipocytes produced less CXCL12, being arguably devoid of HSPC-retaining activity, whereas pioglitazone failed to downregulate Cxcl12 in BM adipocytes. In patients with diabetes on pioglitazone therapy, HSPC mobilization after G-CSF was partially rescued. In summary, pioglitazone reprogrammed BM macrophages and suppressed OSM signaling, but sustained Cxcl12 expression by BM adipocytes could limit full recovery of HSPC mobilization.

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Section: Discussionmentioning

confidence: 75%

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confidence: 64%

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confidence: 99%

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Pharmacologic PPAR-γ Activation Reprograms Bone Marrow Macrophages and Partially Rescues HSPC Mobilization in Human and Murine Diabetes

et al. 2020

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“…The importance of this observation is two‐fold. First, diabetes is characterized by a diabetic stem cell mobilopathy determined, at least in part, by the presence of a bone marrow microangiopathy and by the maladaptive regulation of CXCR4/SDF‐1. Second, both age and risk factors, such as hyperglycaemia, independently associate with the blood levels of progenitor cells, with lower levels in older subjects and those with higher risk factor burden or CVD .…”

Section: Dpp‐4 Inhibition and Stromal Cell‐derived Factor‐1αmentioning

confidence: 99%

The pleiotropic cardiovascular effects of dipeptidyl peptidase‐4 inhibitors

Avogaro

Fadini

2018

Brit J Clinical Pharma

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Patients with Type 2 diabetes have an excess risk for cardiovascular disease. One of the several approaches, included in the guidelines for the management of Type 2 diabetes, is based on dipeptidyl peptidase 4 (DPP-4; also termed CD26) inhibitors, also called gliptins. Gliptins inhibit the degradation of glucagon-like peptide-1 (GLP-1): this effect is associated with increased circulating insulin-to-glucagon ratio, and a consequent reduction of HbA1c. In addition to incretin hormones, there are several proteins that may be affected by DPP-4 and its inhibition: among these some are relevant for the cardiovascular system homeostasis such as SDF-1α and its receptor CXCR4, brain natriuretic peptides, neuropeptide Y and peptide YY. In this review, we will discuss the pathophysiological relevance of gliptin pleiotropism and its translational potential.

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“…Hematopoietic stem/progenitor cells (HSPCs) are reduced in the peripheral blood (PB) of patients with diabetes. 3 Shortage of PB-HSPCs has been attributed to impaired mobilization from the bone marrow (BM), 4,5 a condition deemed mobilopathy. 6 The diabetic BM is characterized by inflammation, neuropathy, and microvascular remodeling, 7,8 which are more profound in patients with limb ischemia.…”

Section: Introductionmentioning

confidence: 99%

Stem cell mobilization with plerixafor and healing of diabetic ischemic wounds: A phase IIa, randomized, double-blind, placebo-controlled trial

Bonora

Cappellari

Mazzucato

et al. 2020

Stem Cells Translational Medicine

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Bone marrow‐derived cells contribute to tissue repair, but traffic of hematopoietic stem/progenitor cells (HSPCs) is impaired in diabetes. We therefore tested whether HSPC mobilization with the CXCR4 antagonist plerixafor improved healing of ischemic diabetic wounds. This was a pilot, phase IIa, double‐blind, randomized, placebo‐controlled trial (NCT02790957). Patients with diabetes with ischemic wounds were randomized to receive a single subcutaneous injection of plerixafor or saline on top of standard medical and surgical therapy. The primary endpoint was complete healing at 6 months. Secondary endpoints were wound size, transcutaneous oxygen tension (TcO2), ankle‐brachial index (ABI), amputations, and HSPC mobilization. Twenty‐six patients were enrolled: 13 received plerixafor and 13 received placebo. Patients were 84.6% males, with a mean age of 69 years. HSPC mobilization was successful in all patients who received plerixafor. The trial was terminated after a preplanned interim analysis of 50% of the target population showed a significantly lower healing rate in the plerixafor vs the placebo group. In the final analysis data set, the rate of complete healing was 38.5% in the plerixafor group vs 69.2% in the placebo group (chi‐square P = .115). Wound size tended to be larger in the plerixafor group for the entire duration of observation. No significant difference was noted for the change in TcO2 and ABI or in amputation rates. No other safety concern emerged. In conclusion, successful HSPC mobilization with plerixafor did not improve healing of ischemic diabetic wounds. Contrary to what was expected, outside the context of hematological disorders, mobilization of diabetic HSPCs might exert adverse effects on wound healing.

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Diabetes mellitus as a poor mobilizer condition

Cited by 26 publications

References 85 publications

Pharmacologic PPAR-γ Activation Reprograms Bone Marrow Macrophages and Partially Rescues HSPC Mobilization in Human and Murine Diabetes

Pharmacologic PPAR-γ Activation Reprograms Bone Marrow Macrophages and Partially Rescues HSPC Mobilization in Human and Murine Diabetes

The pleiotropic cardiovascular effects of dipeptidyl peptidase‐4 inhibitors

Stem cell mobilization with plerixafor and healing of diabetic ischemic wounds: A phase IIa, randomized, double-blind, placebo-controlled trial

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