Administration of Granulocyte Colony-Stimulating Factor After Myocardial Infarction Enhances the Recruitment of Hematopoietic Stem Cell-Derived Myofibroblasts and Contributes to Cardiac Repair

Fujita, Jun; Mori, Mitsuharu; Kawada, Hiroshi; Ieda, Yasuyo; Tsuma, Mitsuyo; Matsuzaki, Yuji; Kawaguchi, Haruko; Yagi, Takashi; Yuasa, Shinsuke; Endo, Jin; Hotta, Tomomitsu; Ogawa, Satoshi; Okano, Hideyuki; Yozu, Ryohei; Ando, Kiyoshi; Fukuda, Keiichi

doi:10.1634/stemcells.2007-0275

Cited by 77 publications

(50 citation statements)

References 25 publications

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“…Fsp1 but not α-smooth muscle actin was found in non-myocyte cells from hypertrophic hearts ( Figure 1C). Activated non-myocyte cells may also be derived from circulating cells (14,(46)(47)(48). Alternatively, the enhanced biomechanical forces resulting from sarcomere protein mutations (7,8) could also provide a local mechanism for activating resident non-myocyte cells.…”

Section: Discussionmentioning

confidence: 99%

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Teekakirikul¹,

Eminaga²,

Toka³

et al. 2010

J. Clin. Invest.

397

342

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Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophynegative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce nonmyocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.

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Section: Discussionmentioning

confidence: 99%

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Teekakirikul¹,

Eminaga²,

Toka³

et al. 2010

J. Clin. Invest.

397

342

View full text Add to dashboard Cite

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“…It has been shown that smooth muscle progenitor cells derived from bone marrow participate in neointimal formation after allotransplantation, post-angioplasty restenosis, and hyperlipidemia-induced atherosclerosis 33) . A recent study demonstrated that G-CSF treatment increased the mobilization of hematopoietic stem cell-derived myofibroblasts in the infarcted heart and enhanced cardiac repair in a mouse AMI model 34) . Increased accumulation of smooth muscle cells in the plaque by G-CSF treatment may result from increased mobilization of hematopoietic stem cell-derived myofibroblasts from bone marrow.…”

Section: Gh Gm3mentioning

confidence: 99%

Appropriate doses of Granulocyte-Colony Stimulating Factor Reduced Atherosclerotic Plaque Formation and Increased Plaque Stability in Cholesterol-Fed Rabbits

Matsumoto

Watanabe

Ueno

et al. 2010

JAT

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Aim:To evaluate the dose-response effects of granulocyte-colony stimulating factor (G-CSF) on atherosclerosis, we examined how G-CSF treatment at different concentrations affects atherosclerotic plaque formation in the aorta of cholesterol-fed rabbits. Methods: Japanese White rabbits (n 8 each) fed on a 1.5% cholesterol diet were subcutaneously injected with G-CSF at 50 (GL), 100 (GM), or 300 g/kg/day (GH) for five days, or with 3 cycles of G-CSF at 100 g/kg/day at 3-week intervals (GM3), or human serum albumin (Control). The extent and composition of atherosclerosis was evaluated 14 weeks after cholesterol feeding. Results: Although G-CSF treatment did not affect plasma lipid levels, the percentage of aortic surface involvement in the GM3 group was significantly decreased (p 0.05) compared with the Control group. Histological analysis revealed that the intima media ratio was also diminished in GM and GM3 groups. The extent of intimal smooth muscle cell accumulation was higher in GL and GM3 groups than in the Control group. TIMP-2 mRNA expression in the aortic tissue was increased by G-CSF treatment. Conclusions: Our results suggest that appropriate doses of G-CSF reduced atherosclerotic plaque formation and increased plaque stability in cholesterol-fed rabbits.J Atheroscler Thromb, 2010; 17:84-96.

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“…22 We found that many hematopoietic stem cell-derived cells, which have a fibroblast-like elongated morphology, are retained at the infarcted myocardium at 7 days post-MI. These cells (A-D) Epicardial and endocardial layer of the infarced area was separately shown in the control and G-CSF treated groups.…”

Section: Discussionmentioning

confidence: 67%

G-CSF Augments Small Vessel and Cell Density in Canine Myocardial Infarction

et al. 2008

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Abstract:We recently reported that granulocyte-colony stimulating factor (G-CSF) prevented cardiac remodeling by mobilization and differentiation of bone marrow-derived cells in murine experimental myocardial infarction (MI). Little is known, however, whether these findings can be reproduced in large animals. The aim of this study is to investigate the effect of G-CSF after MI in canine model. MI was generated in twenty-six beagle dogs by ligation of left anterior descending artery. They were divided into two groups: G-CSF group which received subcutaneous injection of G-CSF (10 µg/kg/day) for 10 days, and the control group with saline injection. After six weeks, they were subjected to echocardiography and catheterization to measure hemodynamic parameters, and histological analysis was performed. No dogs died during the period. No hemodynamic changes were observed between these two groups probably due to the smaller size of the MI than we expected. We found significant increase in wall thickness and higher cell density in G-CSF group. Immunohistochemical staining against α-smooth muscle actin and CD31 revealed increased vessel density mainly in the epicardium in G-CSF group. The number of survived cardiomyocytes in G-CSF group was slightly greater than that in the control group, although it was not statistically significant. These findings suggested G-CSF prevented cardiac remodeling in canine model not by increasing the cardiomyocytes but by increasing the vessel density and cell numbers in the infarcted area. (Keio J Med 57 (3) : 139 -149, september 2008)

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Administration of Granulocyte Colony-Stimulating Factor After Myocardial Infarction Enhances the Recruitment of Hematopoietic Stem Cell-Derived Myofibroblasts and Contributes to Cardiac Repair

Cited by 77 publications

References 25 publications

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Appropriate doses of Granulocyte-Colony Stimulating Factor Reduced Atherosclerotic Plaque Formation and Increased Plaque Stability in Cholesterol-Fed Rabbits

G-CSF Augments Small Vessel and Cell Density in Canine Myocardial Infarction

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