Approaches to therapeutic angiogenesis for ischemic heart disease

Johnson, Takerra; Zhao, Lina; Manuel, Gygeria; Taylor, Herman A.; Liu, Dong

doi:10.1007/s00109-018-1729-3

Cited by 87 publications

(66 citation statements)

References 100 publications

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“…To address this concern, research on therapeutic angiogenesis has been evolving for the past decades [1]. The protein/gene approach, stem/progenitor cell approach, and subsequent microvesicle/exosome approach have been employed as therapies for ischemic diseases [2,3]. Adipose-derived stem cells (ASCs) possess the characteristics of easy acquisition, high proliferative potential, and low immunogenicity, making them attractive candidates for cell-based therapeutics [4,5].…”

Section: Introductionmentioning

confidence: 99%

Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb

et al. 2020

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Background: M2 macrophages and exosomes from adipose-derived stem cells (ASCs) are both reported to promote angiogenesis. However, the possible synergistic effects between exogenous exosomes and endogenous M2 macrophages are poorly understood.Methods: Exosomes were isolated from conditioned medium of normoxic and hypoxic ASCs using the combined techniques of ultrafiltration and size-exclusion chromatography and were identified with nanoparticle tracking analysis and immunoblotting for exosomal markers. Macrophages were collected from the mouse peritoneal cavity. M1 and M2 macrophages were detected by immunoblotting for the intracellular markers inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) and by flow cytometry for the surface markers F4/80, CD86, and CD206. Murine models of Matrigel plug and hindlimb ischemia were employed as in vivo angiogenic assays.(Continued on next page) Results: When M1 macrophages were treated with exosomes from normoxic ASCs (Nor/Exo), and particularly from hypoxic ASCs (Hyp/Exo), the expression of the M1 marker iNOS decreased, and the M2 marker Arg-1 increased in a time-and dosedependent manner. Additionally, a decrease in the M1 surface marker CD86 and an increase in the M2 surface marker CD206 were observed, which suggested that M1 macrophages were polarized to an M2-like phenotype. Conditioned medium from these M2-like macrophages presented lower levels of proinflammatory cytokines and higher levels of proangiogenic factors and promoted endothelial cell proliferation, migration, and tube formation. Furthermore, M2 polarization and angiogenesis were induced upon the administration of exosomes in mouse Matrigel plug and hindlimb ischemia (HLI) models. Interestingly, these exosomal effects were attenuated by using a colony stimulating factor 1 receptor (CSF-1R) inhibitor, BLZ945, in vitro and in vivo. Downregulation of microRNA-21 (miR-21) in hypoxic ASCs reduced the exosomal effects on M2 polarization, Akt phosphorylation, and CSF-1 secretion. A similar reduction in exosomal activity was also observed when exosomes were administered along with BLZ945.Conclusion: Our findings provide evidence that exosomes from ASCs polarize macrophages toward an M2like phenotype, which further enhances the exosomal proangiogenic effects. Exosomal delivery of miR-21 and positive feedback of secreted CSF-1 may be involved in macrophage polarization.

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Section: Introductionmentioning

confidence: 99%

Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb

et al. 2020

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“…HGF provides the best results but is still not sufficient alone [2,9,20,25]. Also, VEGF encoding plasmid seemed to be inefficient in single therapy [9,12,14,16,27]. The poor outcome of therapy aimed on administration of only one angiogenic factor is probably caused by the fact that the angiogenic process requires coordinated expression of multiple genes [9,10,12,14,20].…”

Section: Introductionmentioning

confidence: 99%

“…Also, VEGF encoding plasmid seemed to be inefficient in single therapy [9,12,14,16,27]. The poor outcome of therapy aimed on administration of only one angiogenic factor is probably caused by the fact that the angiogenic process requires coordinated expression of multiple genes [9,10,12,14,20]. However, VEGF is the key factor in angiogenesis by stimulating the proliferation and migration of endothelial cells, which leads to the formation of new vessels.…”

Section: Introductionmentioning

confidence: 99%

Double VEGF/HGF Gene Therapy in Critical Limb Ischemia Complicated by Diabetes Mellitus

Barć

Antkiewicz

Śliwa

et al. 2020

J. of Cardiovasc. Trans. Res.

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Critical leg ischemia (CLI) complicated by diabetes mellitus (DM), which is a very common and dangerous disease, represents the ultimate stage of peripheral arterial disease. Patients are treated with antiplatelet drugs, statins and limb revascularization, but a significant number of patients are not candidate for revascularization. Literature shows that in such cases, gene therapy could be a perfect therapeutic option. The aim of our study was to evaluate efficacy of double vascular endothelial growth factor/ hepatocyte growth factor (VEGF/HGF) gene therapy in patients with CLI complicated by DM. We observed that 90 days after administration, serum level of VEGF and ankle-brachial index increased significantly (p < 0.001) and rest pain decreased significantly compared with the control group (p < 0.002). Moreover considerable improvement in vascularization was observed in computed tomography angiography (P = 0.04). Based on the results of this study, we suggest that the therapy with pIRES/ VEGF165/HGF bicistronic plasmid administration is a safe and effective method of treatment of patients with both CLI and DM.

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“…It is noteworthy that virtually all clinical trials were carried out as a monotherapy. It is reasonable to hypothesize that administration of a combination of 2 or more growth factors may be superior to single agents (40,44). In the present study, the combination of CHIR and FGF1 NPs that act on mechanistically distinct signaling pathways resulted in Figure 7.…”

Section: Discussionmentioning

confidence: 65%

Myocardial protection by nanomaterials formulated with CHIR99021 and FGF1

Fan¹,

Oduk²,

Zhao³

et al. 2020

JCI Insight

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NPs encapsulated with CHIR + FGF1 exerted substantial myocardial protective effects and represents a potentially novel strategy for improving postischemic myocardial protection. Results Identification of chemicals that promote cell cycle activity of human induced pluripotent stem cell-derived cardiomyocytes. Using the BrdU incorporation assay, we screened several chemicals for their capacity to enhance the cell cycle activity of cultured human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We picked hiPSC-CMs because they are easy to handle and represent a practical system for drug testing and screening (5). These chemicals included Ly294002 (PI3K inhibitor) (6), FGF1 (6, 7), SB203580 and VX702 (p38 MAPK inhibitors) (6), KN93 (Ca 2+ /calmodulin-dependent protein kinase II inhibitor) (8), Su1498 (Flk-1 inhibitor) (8), and CHIR99021 (Wnt activator and GSK3α and 3β inhibitor) (8, 9). We found a combination of 5 μM CHIR99021 and 100 ng/mL FGF1 was the most potent treatment to induce cell cycle in hiPSC-derived cardiomyocytes (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.132796DS1). Characterization of CHIR-FGF1-NPs. We have previously shown that PLGA NPs can be used as a platform for slow release (up to 4 weeks) of chemicals to injured animal hearts and that they provide cardioprotection (2). To characterize the long-term cardioprotective function of the FGF/CHIR combination in vivo, we formulated the PLGA NPs with these 2 factors. The size of PLGA NPs was measured using scanning electron microscopy, for both CHIR99021-and FGF1-loaded NPs (Supplemental Figure 2, A and B). Quantification of particle diameter for CHIR-NPs (Supplemental Figure 2C) and FGF1-NPs (Supplemental Figure 2D) yielded values of 123.63 ± 44.48 nm and 129.57 ± 45.94 nm, respectively. The size and shape of CHIR-NPs and FGF1-NPs were uniform. The encapsulation efficiency of CHIR-NPs and FGF1-NPs, i.e., (the amount encapsulated/total amount available) × 100%, was 50.41% and 62.8 ± 1.6%, respectively. The concentration of encapsulated CHIR and FGF1 was 8.07 μg/mg and 1.26 ± 0.03 μg/mg, respectively. Determination of release kinetics of CHIR-and FGF1-loaded NPs as a function of time, using either NanoDrop via UV-Vis spectrophotometer (for CHIR) or ELISA (for FGF1), and the cumulative percentage of CHIR and FGF1 released from NPs, are shown in Supplemental Figure 2, E and F. When 1000 μg of CHIR-and FGF1-loaded NPs were incubated in 1000 μL of Dulbecco's phosphate-buffered saline (DPBS), pH 7.4 at 37°C, 55% of the encapsulated CHIR was released during the first day and 85% by day 15 (Supplemental Figure 2E). In contrast, 55% of the encapsulated FGF1 was released during the initial 3 days, and 63% was released by day 10. Notably, between day 1 and day 30, the release kinetics strictly followed the Korsmeyer-Peppas model for FGF1-NPs (Supplemental Figure 2F). Fitting this model, C t /C 0 = kt n , where C t = concentration at time t; C 0 = equilibrium concentration; ...

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Approaches to therapeutic angiogenesis for ischemic heart disease

Cited by 87 publications

References 100 publications

Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb

Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb

Double VEGF/HGF Gene Therapy in Critical Limb Ischemia Complicated by Diabetes Mellitus

Myocardial protection by nanomaterials formulated with CHIR99021 and FGF1

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