Deferoxamine enhances neovascularization and recovery of ischemic skeletal muscle in an experimental sheep model

Chekanov, Valeri; Nikolaychik, Victor; Maternowski, Michelle A.; Mehran, Roxana; Leon, Martin B.; Adamian, Milena; Moses, Jeffrey W.; Dangas, George; Kipshidze, Nicholas; Akhtar, Masood

doi:10.1016/s0003-4975(02)04122-x

Cited by 16 publications

(9 citation statements)

References 19 publications

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“…DFO has previously been incorporated into an injectable fibrin gel which successfully increased vascular growth in the rabbit ischemic hindlimb or ischemic skeletal muscle in sheep. However, authors did not assess DFO release from this formulation or compare the activity of the fibrin/DFO combination to that of either component alone [26,34]. HUVECs exposed to 100µM DFO chitosan/β-GP gel displayed an increased VEGF expression at 48 and 72 hrs showing that the released DFO was bioactive and that sustained release from the gel contributed to upregulated VEGF expression up to 72 hrs.…”

Section: Discussionmentioning

confidence: 99%

“…DFO is a prolyl-hydroxylase inhibitor which indirectly facilitates active Hypoxia Inducible Factor (HIF) signalling and is thereby capable of eliciting a multifaceted angiogenic response, effected by the transcriptional targets of HIF -1α s ch as VEGF and angiopoietin-2 (ANG-2) [22]. DFO has been shown to increase nuclear HIF-1α acc m ation pre ate expression o VE F in MS s and increase vascular growth and tissue perfusion in models of ischemic disease [23][24][25][26]. Here we present the in vitro development and characterisation of this formulation.…”

Section: Introductionmentioning

confidence: 99%

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Development of a thermoresponsive chitosan gel combined with human mesenchymal stem cells and desferrioxamine as a multimodal pro-angiogenic therapeutic for the treatment of critical limb ischaemia

Hastings

Kelly

Murphy

et al. 2012

Journal of Controlled Release

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Critical limb ischemia (CLI) is a debilitating ischemic disease caused by vascular occlusion. Pro-angiogenic therapeutics have the potential to produce collateral vasculature, delaying or negating the need for amputation or invasive revascularisation. Thermoresponsive hydrogels can provide an in situ depot for the sustained release of drugs and provide protection and cohesion for encapsulated cells. Human Mesenchymal Stem Cells (hMSCs) have demonstrated strong angiogenic potential in vitro and angiogenic efficacy in vivo. Desferrioxamine (DFO), a pharmacological activator of the pro-angiogenic hypoxia inducible factor-1α pathway, has shown pro-angiogenic efficacy in vivo. This study combined hMSCs and DFO with a thermoresponsive chitosan/β-glycerophosphate β-e to nction as an in ecta e m timoda pro-an io enic therape tic or the treatment o his e nderwent a thermo e ation e innin at and provided a sustained, biologically active release of DFO over the space of seven days, whilst permitting the survival, proliferation and migration of encapsulated hMSCs. hMSCs encapsulated in gel containing a 100µM concentration of DFO displayed an upregulation in VEGF expression. The combination of hMSCs and DFO within the gel resulted in a synergistic enhancement in bioactivity, as measured by increased VEGF expression in gel-exposed human umbilical vein endothelial cells. This formulation displays significant potential as an injectable pro-angiogenic therapeutic for the treatment of CLI.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of a thermoresponsive chitosan gel combined with human mesenchymal stem cells and desferrioxamine as a multimodal pro-angiogenic therapeutic for the treatment of critical limb ischaemia

Hastings

Kelly

Murphy

et al. 2012

Journal of Controlled Release

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“…A wide range of natural materials (collagen, fibrin, hyaluronic acid) and approaches involving tissue decellularization have been evaluated (Table 1). [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] A 3-dimensional collagen type I matrix, seeded with human umbilical cord blood mononuclear cells and grafted onto infarcted ventricles in an ischemic murine heart model, showed beneficial effects on left ventricular function and myocardial remodeling. 33 Recently, a similar approach was used successfully in a clinical trial (MAGNUM trial) with a bone marrow mesenchymal stem cell-seeded collagen sponge applied on top of the scarred area, with the aim of regenerating myocardial cells and restoring extracellular matrix function which is deeply altered following myocardial infarction.…”

Section: Tissue-engineered Predifferentiated Cellsmentioning

confidence: 99%

Predifferentiated Adult Stem Cells and Matrices for Cardiac Cell Therapy

Spadaccio

Chachques

Chello³

et al. 2010

Asian Cardiovasc Thorac Ann

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Stem cell therapy is a major field of research worldwide, with increasing clinical application, especially in cardiovascular pathology. However, the best stem cell source and type with optimal safety for functional engraftment remains unclear. An intermediate cardiac precommitted phenotype expressing some of the key proteins of a mature cardiomyocyte would permit better integration into the cardiac environment. The predifferentiated cells would receive signals from the environment, thus achieving gradual and complete differentiation. In cell transplantation, survival and engraftment within the environment of the ischemic myocardium represents a challenge for all types of cells, regardless of their state of differentiation. An alternative strategy is to embed cells in a 3-dimensional structure replicating the extracellular matrix, which is crucial for full tissue restoration and prevention of ventricular remodeling. The clinical translation of cell therapy requires avoidance of potentially harmful drugs and cytokines, and rapid off-the-shelf availability of cells. The combination of predifferentiated cells with a functionalized scaffold, locally releasing molecules tailored to promote in-situ completion of differentiation and improve homing, survival, and function, could be an exciting approach that might circumvent the potential undesired effects of growth factor administration and improve tissue restoration.

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“…Local application of DFO to mobilized latissimus dorsi muscles of adult sheep enhanced neovascularization, specifically capillary density, and recovery of skeletal muscle ischemia. 26 Most recently, in vivo administration of DFO into a distraction gap model of bone repair resulted in increased angiogenesis and markedly improved bone regeneration. 27 The authors first showed that DFO (and to a lesser extent L-mimosine) increased the formation of tube-like structures in a standard Matrigel tube formation assay with HUVECs and promoted endothelial outgrowth from fetal mouse metatarsels in explant culture in vitro.…”

Section: Therapeutic Neovascularizationmentioning

confidence: 99%

Engineering vascularized tissues using natural and synthetic small molecules

2008

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Vascular growth and remodeling are complex processes that depend on the proper spatial and temporal regulation of many different signaling molecules to form functional vascular networks. The ability to understand and regulate these signals is an important clinical need with the potential to treat a wide variety of disease pathologies. Current approaches have focused largely on the delivery of proteins to promote neovascularization of ischemic tissues, most notably VEGF and FGF. Although great progress has been made in this area, results from clinical trials are disappointing and safer and more effective approaches are required. To this end, biological agents used for therapeutic neovascularization must be explored beyond the current well-investigated classes. This review focuses on potential pathways for novel drug discovery, utilizing small molecule approaches to induce and enhance neovascularization. Specifically, four classes of new and existing molecules are discussed, including transcriptional activators, receptor selective agonists and antagonists, natural product-derived small molecules, and novel synthetic small molecules.

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Deferoxamine enhances neovascularization and recovery of ischemic skeletal muscle in an experimental sheep model

Cited by 16 publications

References 19 publications

Development of a thermoresponsive chitosan gel combined with human mesenchymal stem cells and desferrioxamine as a multimodal pro-angiogenic therapeutic for the treatment of critical limb ischaemia

Development of a thermoresponsive chitosan gel combined with human mesenchymal stem cells and desferrioxamine as a multimodal pro-angiogenic therapeutic for the treatment of critical limb ischaemia

Predifferentiated Adult Stem Cells and Matrices for Cardiac Cell Therapy

Engineering vascularized tissues using natural and synthetic small molecules

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