Combination of In Vivo Angiopoietin-1 Gene Transfer and Autologous Bone Marrow Cell Implantation for Functional Therapeutic Angiogenesis

Kobayashi, Koichi S.; Kondo, Takahisa; Inoue, Natsuo; Aoki, Mika; Mizuno, Masaaki; Komori, Kimihiro; Yoshida, Jun; Murohara, Toyoaki

doi:10.1161/01.atv.0000223865.64812.26

Cited by 44 publications

(30 citation statements)

References 56 publications

(69 reference statements)

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“…This was evidenced by an absence of any signs of neoplastic angiogenesis in the necropsy material. Similar results have been observed by other researchers [11,12,14,15]. However, to evaluate the safety of the Ang-1 plasmid administration, longer observation of a larger group of animals is needed.…”

Section: Discussionsupporting

confidence: 88%

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The Formation of Blood Vessel After the Administration of the Plasmid Encoding Ang-1 Gene in Fischer Rats

et al. 2016

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Approximately 1% of patients with peripheral artery disease develop critical lower limb ischemia (CLI) with an unfavorable prognosis. Within one year after the diagnosis, more than 30% of patients with lower limb CLI require amputation [1][2][3][4].The development of endovascular treatment using angioplasty and stents have decreased the amputation rate among patients with CLI. HowCardiovascular disease is the leading cause of death in the Western world and the World Health Organization estimates that over 17 million people worldwide die of cardiovascular disorders each year [1]. There are more than 25 million people in Europe and the United States who have chronic ischemia affecting lower limbs caused by atherosclerotic lesions in the peripheral arteries. A -research concept and design; B -collection and/or assembly of data; C -data analysis and interpretation; D -writing the article; E -critical revision of the article; F -final approval of article AbstractBackground. Chronic limb ischemia is a serious clinical problem. Patients who do not qualify for standard treatment may benefit from novel gene therapies. Objectives. This study evaluated angiogenesis following intramuscular injections of angiogenic plasmid Ang-1 in Fisher rats. Material and Methods. Twenty rats had plasmids injected intramuscularly in their hind limbs. The study group consisted of 10 animals which received the Ang-1 plasmid, while the control group consisted of 10 rats that received an empty plasmid. All the animals were euthanized after 12 weeks and tissue samples from the hind limb thigh muscles and internal organs were harvested for histological and immunohistochemical examinations. To assess the angiogenesis the number of vessels in the hind limb muscles visualized by the SMA and FVIII markers was counted for each animal in five separate microscopic fields. Results. There were no pathological lesions or any signs of neoplastic angiogenesis in any of the 20 rats. The number of vessels visualized by the FVIII marker in the study group was two times higher than in the control group (median: 12, range: 7-25 vs. median: 6, range: 2-15; p < 0.0001). The median estimated that the number of vessels visualized by the SMA marker is 63% higher in the study group compared to the control group (median: 6.5, range: 1-12 vs. median: 4, range: 0-10; p = 0.0008). Conclusions. Intramuscular injections of Ang-1 plasmids induced angiogenesis in the rat hind limb muscles (Adv Clin Exp Med 2016, 25, 4, 611-615).

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Section: Discussionsupporting

confidence: 88%

“…VEGF and Ang-1 may also activate the expression of proangiogenic genes. Moreover, Ang-1 is also known to stabilize newly formed vessels [14][15][16][17].…”

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confidence: 99%

The Formation of Blood Vessel After the Administration of the Plasmid Encoding Ang-1 Gene in Fischer Rats

et al. 2016

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“…In this view, administration of a plasmid encoding Ang-1 with autologous bone marrow cell injection enhances neovascularization in a rabbit hindlimb ischemia model compared with BM-MNC implantation alone. 35 These results suggest that the increase efficiency of cotherapy results from the release of Ang-1 by SMPCs, leading to the activation of Tie2 at the EPC surface and subsequently to the activation of EPC-related functions. Nevertheless, it is likely that SMPCs have other effect than just a secretion of Ang-1.…”

Section: Discussionmentioning

confidence: 77%

Coadministration of Endothelial and Smooth Muscle Progenitor Cells Enhances the Efficiency of Proangiogenic Cell-Based Therapy

Foubert

Matrone

Souttou

et al. 2008

Circulation Research

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Abstract-Cell-based therapy is a promising approach designed to enhance neovascularization and function of ischemic tissues. Interaction between endothelial and smooth muscle cells regulates vessels development and remodeling and is required for the formation of a mature and functional vascular network. Therefore, we assessed whether coadministration of endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs) can increase the efficiency of cell therapy. Unilateral hindlimb ischemia was surgically induced in athymic nude mice treated with or without intravenous injection of EPCs (0.5ϫ10 6 ), SMPCs (0.5ϫ10 6 ) and EPCsϩSMPCs (0.25ϫ10 6 ϩ0.25ϫ10 6 ). Vessel density and foot perfusion were increased in mice treated with EPCsϩSMPCs compared to animals receiving EPCs alone or SMPCs alone (PϽ0.001). In addition, capillary and arteriolar densities were enhanced in EPCϩSMPC-treated mice compared to SMPC and EPC groups (PϽ0.01). We next examined the role of Ang-1/Tie2 signaling in the beneficial effect of EPC and SMPC coadministration. Small interfering RNA directed against Ang-1-producing SMPCs or Tie2-expressing EPCs blocked vascular network formation in Matrigel coculture assays, reduced the rate of incorporated EPCs within vascular structure, and abrogated the efficiency of cell therapy. Production of Ang-1 by SMPCs activates Tie2-expressing EPCs, resulting in increase of EPC survival and formation of a stable vascular network. Subsequently, the efficiency of EPC-and SMPC-based cotherapy is markedly increased. Therefore, coadministration of different types of vascular progenitor cells may constitute a novel therapeutic strategy for improving the treatment of ischemic diseases.

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“…Recent studies have shown that a combination of stem cell transplantation and angiogenic or antiapoptotic factors or genes synergistically enhanced neovascularization in ischemic tissues compared with each therapy alone. 27,28 Coadministration of several growth factors enhanced ESC engraftment and hostspecific differentiation in hearts with myocardial infarction. 29 Thus, combination therapy could be used to enhance the angiogenic efficacy of hESC-EC transplantation.…”

Section: Cho Et Al Hesc-derived Functional Endothelial-like Cells 2415mentioning

confidence: 99%

Improvement of Postnatal Neovascularization by Human Embryonic Stem Cell–Derived Endothelial-Like Cell Transplantation in a Mouse Model of Hindlimb Ischemia

et al. 2007

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Background-We established an efficient preparation method to obtain endothelial-like cells (ECs) from human embryonic stem cells (hESCs) and tested whether these hESC-ECs would show therapeutic potential for treatment of hindlimb ischemia. Methods and Results-ECs differentiated from hESCs were obtained by mechanical isolation and cell sorting for von Willebrand factor. The isolated hESC-ECs maintained endothelial cell-specific characteristics such as endothelial marker expression and capillary formation. One day after surgical induction of hindlimb ischemia in athymic mice, hESC-ECs were injected intramuscularly into ischemic limbs. Four weeks after treatment, hESC-EC treatment significantly increased limb salvage (36%) compared with treatment with medium (0%). In addition, laser Doppler imaging showed that the ratio of blood perfusion (ischemic to normal limb) was increased significantly (PϽ0.01) by hESC-EC treatment (0.511Ϯ0.167) compared with medium injection (0.073Ϯ0.061). Capillary and arteriole densities were 658Ϯ190/mm 2 and 30Ϯ11/mm 2 in the hESC-EC group, respectively, whereas those in the medium group were 392Ϯ118/mm 2 and 16Ϯ8/mm

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Combination of In Vivo Angiopoietin-1 Gene Transfer and Autologous Bone Marrow Cell Implantation for Functional Therapeutic Angiogenesis

Cited by 44 publications

References 56 publications

The Formation of Blood Vessel After the Administration of the Plasmid Encoding Ang-1 Gene in Fischer Rats

The Formation of Blood Vessel After the Administration of the Plasmid Encoding Ang-1 Gene in Fischer Rats

Coadministration of Endothelial and Smooth Muscle Progenitor Cells Enhances the Efficiency of Proangiogenic Cell-Based Therapy

Improvement of Postnatal Neovascularization by Human Embryonic Stem Cell–Derived Endothelial-Like Cell Transplantation in a Mouse Model of Hindlimb Ischemia

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