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Controlled release of stromal cell-derived factor-1 for enhanced progenitor response in ischemia

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  • Pathologists Bio-Medical Labs
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... Wang and colleagues reported that the SDF-1/CXCR4 pathway was critical for MSCs to migrate and improve the functional restoration of SG in mice with Sjögren's-like disease 36 . Moreover, local injections of SDF-1 mobilized progenitor cells from bone marrow to the circulation and enhanced vascularisation 37 . The relationship between CD26 and angiogenesis remains controversial. ...
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In separate studies, an extract of soluble intracellular contents from whole bone marrow cells, named Bone Marrow (BM) Soup, was reported to either improve cardiac or salivary functions post-myocardial infarction or irradiation (IR), respectively. However, the active components in BM Soup are unknown. To demonstrate that proteins were the active ingredients, we devised a method using proteinase K followed by heating to deactivate proteins and for safe injections into mice. BM Soup and deactivated BM Soupwere injected into mice that had their salivary glands injured with 15Gy IR. Control mice received either injections of saline or were not IR. Results at week 8 post-IR showed the deactivated BM Soupwas no better than injections of saline, while injections of native BM Soup restored saliva flow, protected salivary cells and blood vessels from IR-damage. Protein arrays detected several angiogenesis-related factors (CD26, FGF, HGF, MMP-8, MMP-9, OPN, PF4, SDF-1) and cytokines (IL-1ra, IL-16) in BM Soup. In conclusion, the native proteins (but not the nucleic acids, lipids or carbohydrates) were the therapeutic ingredients in BM Soup for functional salivary restoration following IR. This molecular therapy approach has clinical potential because it is theoretically less tumorigenic and immunogenic than cell therapies.
... While alginate is an abundant, naturally-derived biomaterial, with attractive properties for tissue engineering, it is not an extracellular matrix component. To better mimic the native tissue microenvironment, Kuraitis et al. incorporated stromal cell-derived factor-1 (SDF-1) in alginate microspheres which they then embedded in an injectable collagen matrix and delivered in a rabbit hindlimb ischemia model [162,163]. Similarly, alginate microparticles in a collagen-fibronectin scaffold have been used to co-deliver VEGF and endothelial cells [155]. Combinations of several growth factors and/or cell types may act in a synergistic manner for muscle repair. ...
... Unless regenerative therapies are employed, the best one can hope for is to restore functionality to the borderzone and limit its expansion, thereby protecting the remote, normal myocardium. The data we report here indirectly supports that of other investigations, where injected SDF has been shown to improve the molecular dynamics of the borderzone and preserve ventricular function after MI. 7,[24][25][26] Although we have shown statistically significant reduction in the elastic modulus of the ventricular strips treated with ESA, with good confidence intervals for each specimen sampled, there are some limitations. First, our technique for obtaining stress-strain relationships was through uniaxial testing from longitudinally sectioned ventricle. ...
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The biomechanical response to a myocardial infarction consists of ventricular remodeling that leads to dilatation, loss of contractile function, abnormal stress patterns, and ultimately heart failure. We hypothesized that intramyocardial injection of our previously designed pro-angiogenic chemokine, an engineered stromal cell-derived factor-1α analog (ESA), improves mechanical properties of the heart after infarction. Male rats (n = 54) underwent either sham surgery (n = 17) with no coronary artery ligation or ligation of the left anterior descending artery (n = 37). The rats in the myocardial infarction group were then randomized to receive either saline (0.1 mL, n = 18) or ESA (6 μg/kg, n = 19) injected into the myocardium at 4 predetermined spots around the border zone. Echocardiograms were performed preoperatively and before the terminal surgery. After 4 weeks, the hearts were explanted and longitudinally sectioned. Uniaxial tensile testing was completed using an Instron 5543 Microtester. Optical strain was evaluated using custom image acquisition software, Digi-Velpo, and analyzed in MATLAB. Compared with the saline control group at 4 weeks, the ESA-injected hearts had a greater ejection fraction (71.8% ± 9.0% vs 55.3% ± 12.6%, P = .0004), smaller end-diastolic left ventricular internal dimension (0.686 ± 0.110 cm vs 0.763 ± 0.160 cm, P = .04), greater cardiac output (36 ± 11.6 mL/min vs 26.9 ± 7.3 mL/min, P = .05), and a lower tensile modulus (251 ± 56 kPa vs 301 ± 81 kPa, P = .04). The tensile modulus for the sham group was 195 ± 56 kPa, indicating ESA injection results in a less stiff ventricle. Direct injection of ESA alters the biomechanical response to myocardial infarction, improving the mechanical properties in the postinfarct heart.
... Separate studies have shown that an increase in circulating CXCR4+ cells coincides with the temporal expression of rSDF-1α in the heart following MI [8,9]. In addition, elevating SDF-1α concentrations in the blood has been shown to mobilize BMCs into the circulation [36]. Since we report the number of PKH+ BMCs in the blood as a percentage of total BMCs in the blood, an increase in this percentage may indicate that systemic concentrations of SDF-1α are high enough to prevent circulating PKH+ BMCs from homing to other organs, such as the bone marrow or spleen [37,38], but not high enough to mobilize native BMCs from SDF-1α gradients in the bone marrow. ...
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Poor cell engraftment in the myocardium is a limiting factor towards the use of bone marrow derived cells (BMCs) to treat myocardial infarction (MI). In order to enhance the engraftment of circulating BMCs in the myocardium following MI, we have developed in situ forming hyaluronic acid (HA) hydrogels with degradable crosslinks to sustain the release of recombinant stromal cell-derived factor-1 alpha (rSDF-1α) and HA to the injured myocardium. Both rSDF-1α and the crosslinkable HA macromer stimulate BMC chemotaxis up to 4-fold in vitro through CXCR4 and CD44 receptor signaling, respectively. Moreover, the HA macromer binds rSDF-1α with a dissociation constant of 36 ± 5 μM through electrostatic interaction. When formed into hydrogels via photoinitiated crosslinking, release of encapsulated rSDF-1α and crosslinked HA was sustained for over 7 days, and these molecules significantly increased BMC chemotaxis in vitro. When applied to the heart following experimental MI in mice, the HA gel containing rSDF-1α significantly increased the number of systemically infused BMCs in the heart by ~8.5 fold after 7 days, likely through both systemic and local effects of released molecules. We conclude that sustained release of rSDF-1α and HA from our engineered HA hydrogels enhances BMC homing to the remodeling myocardium better than delivery of rSDF-1α alone.
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Intracoronary transfer of autologous bone marrow cells (BMCs) promotes recovery of left ventricular systolic function in patients with acute myocardial infarction. Although the mechanisms of this effect remain to be established, homing of BMCs into the infarcted myocardium is probably a critical early event. We determined BMC biodistribution after therapeutic application in patients with a first ST-segment-elevation myocardial infarction who had undergone stenting of the infarct-related artery. Unselected BMCs were radiolabeled with 100 MBq 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) and infused into the infarct-related coronary artery (intracoronary; n=3 patients) or injected via an antecubital vein (intravenous; n=3 patients). In 3 additional patients, CD34-positive (CD34+) cells were immunomagnetically enriched from unselected BMCs, labeled with 18F-FDG, and infused intracoronarily. Cell transfer was performed 5 to 10 days after stenting. More than 99% of the infused total radioactivity was cell bound. Nucleated cell viability, comparable in all preparations, ranged from 92% to 96%. Fifty to 75 minutes after cell transfer, all patients underwent 3D PET imaging. After intracoronary transfer, 1.3% to 2.6% of 18F-FDG-labeled unselected BMCs were detected in the infarcted myocardium; the remaining activity was found primarily in liver and spleen. After intravenous transfer, only background activity was detected in the infarcted myocardium. After intracoronary transfer of 18F-FDG-labeled CD34-enriched cells, 14% to 39% of the total activity was detected in the infarcted myocardium. Unselected BMCs engrafted in the infarct center and border zone; homing of CD34-enriched cells was more pronounced in the border zone. 18F-FDG labeling and 3D PET imaging can be used to monitor myocardial homing and biodistribution of BMCs after therapeutic application in patients.
An acellular matrix-bound ligand enhances the mobilization, recruitment and therapeutic effects of circulating progenitor cells in a hindlimb ischemia model
  • E J Suuronen
  • P Zhang
  • D Kuraitis
  • X Cao
  • A Melhuish
  • D Mckee
  • F Li
  • T G Mesana
  • J P Veinot
  • M Ruel
E.J. Suuronen, P. Zhang, D. Kuraitis, X. Cao, A. Melhuish, D. McKee, F. Li, T.G. Mesana, J.P. Veinot, M. Ruel, An acellular matrix-bound ligand enhances the mobilization, recruitment and therapeutic effects of circulating progenitor cells in a hindlimb ischemia model, FASEB J. 23 (2009) 1447-1458. doi:10.1016/j.jconrel.2011.09.019