Attenuation of cardiac hypertrophy by G‐<scp>CSF</scp> is associated with enhanced migration of bone marrow‐derived cells

Hüber, Bruno; Beetz, Nick Lasse; Laskowski, Alexandra; Ziegler, Tilman; Grabmaier, Ulrich; Kupatt, Christian; Herbach, Nadja; Wanke, Rüdiger; Franz, Wolfgang M.; Maßberg, Steffen; Brunner, Stefan

doi:10.1111/jcmm.12494

Cited by 11 publications

(10 citation statements)

References 32 publications

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“…Thus, CD45+CD34+VLA-4+ cells were recruited to the infarcted heart area of mice with acute VMC, which might contribute to the repair of myocardial tissue. It has previously been reported that the percentage of CD34+CD45+VLA-4+ cells is increased in the murine CVB3-induced DCM heart, and, thus, higher numbers of CD34+CD45+VLA-4+ cells lead to beneficial anti-apoptotic effects and significantly improve cardiac function after G-CSF-induced cell mobilization in mice [18], which is in agreement with our study. There is evidence that MSCs secrete multiple cytokines and promote cardiac stem cell proliferation and differentiation through paracrine effects, induce new myocardial cells, access mitosis of the cell cycle, and ultimately promote endogenous myocardial regeneration.…”

Section: Discussionsupporting

confidence: 82%

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Increased Mobilization of CD45+CD34+VLA-4+ Cells in Acute Viral Myocarditis Induced by Coxsackievirus B3

Gao

Wei²,

Deng³

et al. 2017

Cardiology

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Objectives: Bone marrow-derived cells (BMCs) have recently been identified to play a vital role in repairing damaged myocardium; however, it is not known whether or not mobilization of BMCs is involved in the pathogenesis of acute viral myocarditis (VMC). Thus, we analyzed the expression of CD45+CD34+VLA-4+ cells and vascular cell adhesion protein-1 (VCAM-1) in a murine model of acute VMC. Methods: Male BALB/c mice were intraperitoneally infected with coxsackievirus B3 to establish acute VMC. The frequency of CD45+CD34+VLA-4+ cells in the heart, peripheral blood, and bone marrow was examined by flow cytometry 3, 7, 14, and 28 days after injection. Cardiac VCAM-1 and pathology scores were determined by immunohistochemistry, and myocardial VCAM-1, IL-1β, and TNF-α were analyzed by RT-PCR and Western blot. Results: In mice with acute VMC, the CD45+CD34+VLA-4+ cell population in the heart was significantly increased by day 7 and then decreased; in contrast, the CD45+CD34+VLA-4+ cell population decreased in the bone marrow and peripheral blood by day 3 and then increased. High expression of VCAM-1 was detected in the heart in parallel with CD45+CD34+VLA-4+ cell expression. Conclusions: In mice with acute VMC, VCAM-1-induced CD45+CD34+VLA-4+ cell mobilization into the injured heart is involved in the repair of injured myocardium.

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Section: Discussionsupporting

confidence: 82%

“…It has been reported that BMC migration to the heart correlates with VCAM-1 and promotes BMC mobilization to the diseased heart [18]. Koch et al [23] demonstrated that MSCs home to infracted heart tissue via the VCAM-1/VLA-4 axis.…”

Section: Discussionmentioning

confidence: 99%

Increased Mobilization of CD45+CD34+VLA-4+ Cells in Acute Viral Myocarditis Induced by Coxsackievirus B3

Gao

Wei²,

Deng³

et al. 2017

Cardiology

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“…In the past years, regeneration of ischemic myocardial tissue has been attempted using bone marrow-derived stem cells (BMCs) and wide variety of stem cells As an alternative to the direct intramyocardial injection, mobilization of BMCs using growth factors, such as the hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) or even IL10, have been successfully utilized 34, 43 . Migration of circulating mobilized BMCs from the bloodstream into the damaged tissue is suggested to play a key role for tissue regeneration.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium

et al. 2017

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Background Activated fibroblasts (myofibroblasts; myoFBs) play critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPC) in pressure overload (PO)-induced cardiac fibrosis. We have earlier shown that interleukin-10 (IL10) suppresses PO-induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC-mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits PO-induced homing of BM-FPCs to the heart and their trans-differentiation to myoFBs and thus attenuates cardiac fibrosis. Methods Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction (TAC). To determine the bone marrow origin, chimeric mice were created using eGFP WT mice marrow to the IL10KO mice. For mechanistic studies, fibroblast progenitor cells were isolated from mouse bone marrow. Results Pressure overload enhanced bone marrow fibroblast progenitor cell (BM-FPC) mobilization and homing in IL10KO mice compared to WT mice. Furthermore, WT bone marrow (from eGFP mice) transplantation in BM-depleted IL10KO mice (IL10KO chimeric mice) reduced TAC-induced BM-FPC mobilization compared to IL10KO mice. GFP co-staining with αSMA or collagen 1α in left ventricular tissue sections of IL10KO chimeric mice suggest that myofibroblasts were derived from bone marrow post-TAC. Finally, WT-BMT in IL10KO mice inhibited TAC-induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited TGFβ-induced transdifferentiation and fibrotic signaling in WT BM-FPC in vitro. Furthermore, fibrosis-associated miRNAs expression was highly upregulated in IL10KO-FPCs compared to WT-FPCs. PCR-based selective miRNA analysis revealed that TGFβ-induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145 and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on TGFβ-induced fibrotic signaling in BM-FPC. Conclusion Our findings suggest that IL10 inhibits BM-FPC homing and trans-differentiation to myofibroblasts in pressure overloaded myocardium. Mechanistically for the first time we showed that IL10 suppresses Smad-miRNA-21 mediated activation of BM-FPCs and thus modulates cardiac fibrosis.

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“…One of the factors that may contribute to the recovery of compliance following G-CSF administration is the reduction of the fibrosis. Previous studies have demonstrated that G-CSF administration has protective effects against cardiac remodeling and acts to reduce cardiac hypertrophy [ 45 , 46 ]. Thus, we suggest that G-CSF acts as a mediator against cardiac hypertrophy, presenting a promising therapeutic option for individuals with diabetic cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Administration of granulocyte-colony stimulating factor accompanied with a balanced diet improves cardiac function alterations induced by high fat diet in mice

Daltro

Alves

Castro

et al. 2015

BMC Cardiovasc Disord

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Background/ObjectivesHigh fat diet (HFD) is a major contributor to the development of obesity and cardiovascular diseases due to the induction of cardiac structural and hemodynamic abnormalities. We used a model of diabetic cardiomyopathy in C57Bl/6 mice fed with a HFD to investigate the effects of granulocyte-colony stimulating factor (G-CSF), a cytokine known for its beneficial effects in the heart, on cardiac anatomical and functional abnormalities associated with obesity and type 2 diabetes.MethodsGroups of C57Bl/6 mice were fed with standard diet (n = 8) or HFD (n = 16). After 36 weeks, HFD animals were divided into a group treated with G-CSF + standard diet (n = 8) and a vehicle control group + standard diet (n = 8). Cardiac structure and function were assessed by electrocardiography, echocardiography and treadmill tests, in addition to the evaluation of body weight, fasting glicemia, insulin and glucose tolerance at different time points. Histological analyses were performed in the heart tissue.ResultsHFD consumption induced metabolic alterations characteristic of type 2 diabetes and obesity, as well as cardiac fibrosis and reduced exercise capacity. Upon returning to a standard diet, obese mice body weight returned to non-obese levels. G-CSF administration accelerated the reduction in of body weight in obese mice. Additionally, G-CSF treatment reduced insulin levels, diminished heart fibrosis, increased exercise capacity and reversed cardiac alterations, including bradycardia, elevated QRS amplitude, augmented P amplitude, increased septal wall thickness, left ventricular posterior thickening and cardiac output reduction.ConclusionOur results indicate that G-CSF administration caused beneficial effects on obesity-associated cardiac impairment.

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Attenuation of cardiac hypertrophy by G‐CSF is associated with enhanced migration of bone marrow‐derived cells

Cited by 11 publications

References 32 publications

Increased Mobilization of CD45+CD34+VLA-4+ Cells in Acute Viral Myocarditis Induced by Coxsackievirus B3

Increased Mobilization of CD45+CD34+VLA-4+ Cells in Acute Viral Myocarditis Induced by Coxsackievirus B3

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium

Administration of granulocyte-colony stimulating factor accompanied with a balanced diet improves cardiac function alterations induced by high fat diet in mice

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