Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis

Sata, Masataka; Saiura, Akio; Kunisato, Atsushi; Tojo, Akihiro; Okada, Seiji; Tokuhisa, Takeshi; Hirai, Hisamaru; Makuuchi, Masatoshi; Hirata, Yasunobu; Nagai, Ryozo

doi:10.1038/nm0402-403

Cited by 1,068 publications

(962 citation statements)

References 33 publications

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“…We then tested whether inflammatory cell infiltration and ROS are involved in the development of neointimal hyperplasia, and because bone marrow-derived cells reportedly contribute to neointima formation [24], we also tested a bone marrow transplantation (BMT) model using CGRP-/-mice. Finally, we investigated the effects of CGRP on the proliferation and migration of VSMCs.…”

Section: Introductionmentioning

confidence: 99%

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Yang

Sakurai

Kamiyoshi

et al. 2013

Journal of Molecular and Cellular Cardiology

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Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene.Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule.We compared the effect of CGRP deficiency on neointima formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP-/-) mice. We found that neointima formation after vascular injury was markedly enhanced in CGRP-/-mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointima formation in CGRP-/-mice. In vitro analysis showed CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease.

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Section: Introductionmentioning

confidence: 99%

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Yang

Sakurai

Kamiyoshi

et al. 2013

Journal of Molecular and Cellular Cardiology

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“…For reprints contact: Reprints@AlphaMedPress.com 700 Bone Marrow-Derived Fibroblasts Recruited into Fibrotic Lesions transplantation of bone marrow (BM), hematopoietic stem cells or nonhematopoietic mesenchymal stem cells, muscle [7][8][9][10][11], heart [12][13][14], liver [15][16][17][18][19], vascular cells [20,21], and other mesenchymal cells [22][23][24] of donor origin have been detected. Investigators revealed that BM-derived cells can be progenitors for tissue fibroblasts that are recruited through the circulation to populate peripheral organs [25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

In Vivo Characterization of Bone Marrow–Derived Fibroblasts Recruited into Fibrotic Lesions

et al. 2005

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Fibroblasts, which are widely distributed and play a key part in tissue fibrosis, are phenotypically and functionally heterogeneous. Recent studies reported that bone marrow can be a source of tissue fibroblast. In the study reported here, we investigated in vivo characterization of bone marrowderived fibroblasts recruited into various fibrotic lesions. Mice were engrafted with bone marrow isolated from transgenic mice expressing green fluorescent protein (GFP), and fibrotic lesions were induced by cancer implantation (skin), excisional wounding (skin), and bleomycin administration (lung). A small population of GFP + fibroblast was found even in nonfibrotic skin (8.7% ± 4.6%) and lung (8.9% ± 2.5%). The proportion of GFP + fibroblasts was significantly increased after cancer implantation (59.7% ± 16.3%) and excisional wounding (32.2% ± 4.8%), whereas it was not elevated after bleomycin administration (7.1% ± 2.4%). Almost all GFP + fibroblasts in fibrotic lesions expressed type I collagen, suggesting that bone marrow-derived fibroblasts would contribute to tissue fibrosis. GFP + fibroblasts expressed CD45, Thy-1, and α-smooth muscle actin at various proportions. Our results suggested that bone marrow-derived fibroblasts expressed several fibroblastic markers in vivo and could be efficiently recruited into fibrotic lesions in response to injurious stimuli; however, the degree of recruitment frequency might depend on the tissue microenvironment. Stem Cells 2005;23:699-706

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“…The transformed cells could then provide prolonged expression of a therapeutic protein(s) chosen to aid the wound healing process and thereby minimize vessel reocclusion. The recent report 13 that bone marrow cells home to sites of vascular injury and constitute a significant portion of the neointimal cells in a vascular lesion suggests that extended expression of therapeutic proteins may be required to target these progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

Takahashi

Palmer-Opolski²,

Smith

et al. 2003

Gene Ther

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Metallic stents coated with a polyurethane emulsion containing plasmid DNA were implanted in rabbit iliac arteries to evaluate transgene delivery and expression in the vessel wall. The expression of the plasmid-encoded marker genes, b-galactosidase, luciferase and green fluorescence protein (GFP), were evaluated at 7 days after implantation. In all cases, plasmid transfer was confined to the vessel wall at the site of stent implantation, plasmid DNA was not observed in vessel segments immediately proximal or distal to the stent and dissemination of plasmid DNA to lung, liver or spleen was not observed. Expression of transgenes occurred only in vessel segments in contact with the stent and analysis of the GFP expression pattern revealed a high frequency of marker protein-positive cells occurring at or near the luminal surface. The extent of transgene expression was dependent upon the quantity of DNA loaded onto the stent and no signal was detected in vessel segments that received polymer-coated stents lacking plasmid DNA. Of significance, colocalization studies identified transgene expression not only in vascular smooth muscle cells but also in macrophages. Hence, polymer-coated stents provide a new capability for transgene delivery to immune cells that are believed to contribute to the development of in-stent restenosis.

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Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis

Cited by 1,068 publications

References 33 publications

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

In Vivo Characterization of Bone Marrow–Derived Fibroblasts Recruited into Fibrotic Lesions

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

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