Activation of c‐kit is necessary for mobilization of reparative bone marrow progenitor cells in response to cardiac injury

Fazel, Shafie; Chen, Liwen; Angoulvant, Denis; Li, Shuhong; Weisel, Richard D.; Keating, Armand; Li, Ren‐Ke

doi:10.1096/fj.07-8636com

Cited by 69 publications

(68 citation statements)

References 60 publications

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“…As the ligand of c-kit, soluble SCF is increased in the bone marrow after myocardial ischemia/reperfusion injury, leading to EPC mobilization and improvement in myocardial neovascularization and cardiac function. 26 Furthermore, peri-infarct injections of soluble SCF increased c-kit ϩ stem cell recruitment to the infarcted heart after intravenous administration of bone marrow-derived stem cells. 27 Although this effect lasted 72 hours, no functional benefit was observed.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-Specific Overexpression of Human Stem Cell Factor Improves Cardiac Function and Survival After Myocardial Infarction in Mice

Xiang

Hammoud

et al. 2009

Circulation

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Background-Soluble stem cell factor (SCF) has been shown to mobilize bone marrow stem cells and improve cardiac repair after myocardial infarction (MI). However, the effect of membrane-associated SCF on cardiac remodeling after MI is not known. The present study investigated the effects of cardiomyocyte-specific overexpression of the membrane-associated isoform of human SCF (hSCF) on cardiac function after MI. Methods and Results-A novel mouse model with tetracycline-inducible and cardiac-specific overexpression of membrane-associated hSCF was generated. MI was induced by left coronary artery ligation. Thirty-day mortality after MI was decreased in hSCF/tetracycline transactivator (tTA) compared with wild-type mice. In vivo cardiac function was significantly improved in hSCF/tTA mice at 5 and 30 days after MI compared with wild-type mice. Endothelial progenitor cell recruitment and capillary density were increased and myocardial apoptosis was decreased in the peri-infarct area of hSCF/tTA mice. Myocyte size was decreased in hSCF/tTA mice 30 days after MI compared with WT mice. Furthermore, hSCF overexpression promoted de novo angiogenesis as assessed by matrigel implantation into the left ventricular myocardium. Conclusions-Cardiomyocyte-specific overexpression of hSCF improves myocardial function and survival after MI.These beneficial effects of hSCF may result from increases in endothelial progenitor cell recruitment and neovascularization and decreases in myocardial apoptosis and cardiac remodeling.

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Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-Specific Overexpression of Human Stem Cell Factor Improves Cardiac Function and Survival After Myocardial Infarction in Mice

Xiang

Hammoud

et al. 2009

Circulation

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“…2 Not only cells expressing c-kit are mobilized from BM in the circulation in response to hypoxia, but they are also found in the remodeled lung vessel wall in PAH (Figure 3 and Hayashida et al, 7 Davie et al, 8 Farha et al, 12 Spees et al, 24 and Sata et al 31 ). Activation of c-kit was reported as necessary for mobilization of reparative BM progenitor cells 32 and for the remodeling of blood vessels from these progenitor cells. 3,27 Recently, a role of c-kit ϩ progenitors in hypoxia-induced vascular remodeling 26,33 was evidenced: stromal derived factor-1 (SDF-1/CXCL12) and its receptors CXCR4 and CXCR7 have been shown to be critical for homing of hematopoietic c-kit ϩ progenitor cells in the perivascular niche, including in chronic hypoxia-exposed mice.…”

Section: Discussionmentioning

confidence: 99%

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Launay

Hervé

Crinon

et al. 2012

Blood

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Pulmonary arterial hypertension (PAH) is IntroductionPulmonary arterial hypertension (PAH) is a rare but fatal disease, often of unknown origin, characterized by progressive increase in pulmonary vascular resistance and remodeling associated with vasoconstriction. 1 PAH is histologically characterized by a neomuscularization of small pulmonary arteries with intimal thickening, medial hypertrophy, adventitial proliferation, and abnormal extracellular matrix deposition. The progression of vascular remodeling results in vascular lumen narrowing, increased pulmonary artery resistance, hypoxia, and right heart hypertrophy, although the molecular pathways initiating this remodeling are not clearly established.On the one hand, stem cells, resident or not, may give rise to a significant proportion of differentiating/proliferating smooth muscle cells (SMCs) that contribute to intimal hyperplasia in lung vascular remodeling. 2 Moreover, genetic ablation of the transmembrane tyrosine kinase receptor for stem cell factor/c-kit pathway results in a marked reduction in intimal hyperplasia in animal models of vascular injury; conversely, wild-type (WT) bone marrow (BM) reconstitution in c-kit mutant mice led to intimal hyperplasia comparable with WT animals. 3 Pharmacologic antagonism of the c-kit pathway with STI-571 (imatinib mesylate; Gleevec) also results in a marked reduction in hyperplasia. 3 Mobilization of c-kit expressing cells from BM to blood circulation is a physiologic response to hypoxia. Increasing evidence supports the idea that these progenitor cells of BM origin may also contribute to vascular wall remodeling that is characteristic of PAH. [4][5][6][7][8] However, it is unclear, whether this entry of progenitors represents a protective or a worsening process in the development of PAH. 9 Other observations have also identified an association between PAH and BMrelated hematologic disorders 10 : in proliferative disorders of the hematopoietic stem cells such as myeloproliferative cancers, there is an unexplained high incidence of PAH. PAH is now a recognized complication of BM transplantation for leukemia, 11 chronic myeloproliferative disorders, 12 or in the treatment of malignant infantile osteopetrosis. 13 On the other hand, serotonin (5-hydroxytryptamine ) is associated with the pathogenesis of PAH. 14 Therapeutic drugs with PAH as a side effect, such as the amphetamine derivative and anorexigen dexfenfluramine, are potent 5-HT releasers acting at 5-HT transporter (SERT) and/or agonists at 5-HT receptors (5-HTRs). 15 An over-expression of 5-HT 2B Rs is observed in PAH. 16 Blockade of 5-HT 2B Rs using independent approaches, either genetic (5-HT 2B R knock-out mice; 5-HT 2B Ϫ/Ϫ ) or pharmacologic (5-HT 2B antagonist RS-12744) inactivation, completely prevented the development of hypoxia-induced pulmonary hypertension in mice. 16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduc...

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“…Furthermore, the number of c-Kit ϩ cells in the peri-infarct area was similarly elevated by G-CSF/SCF treatment regardless of age. These cells have the potential to originate either from bone marrow 1,35 or from the heart itself, where they represent endogenous cardiac stem cells. 36 There is increasing support for the presence of an …”

Section: Discussionmentioning

confidence: 99%

Aging Impairs the Beneficial Effect of Granulocyte Colony-Stimulating Factor and Stem Cell Factor on Post-Myocardial Infarction Remodeling

Lehrke¹,

Mazhari²,

Durand³

et al. 2006

Circulation Research

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Abstract-Granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) are potential new therapies to ameliorate post-myocardial infarction (post-MI) remodeling, as they enhance endogenous cardiac repair mechanisms and decrease cardiomyocyte apoptosis. Because both of these pathways undergo alterations with increasing age, we hypothesized that therapeutic efficacy of G-CSF and SCF is impaired in old versus young adult rats. MI was induced in 6-and 20-month-old rats by permanent ligation of the left coronary artery. In young animals, G-CSF/SCF therapy stabilized and reversed a decline in cardiac function, attenuated left ventricular dilation, decreased infarct size, and reduced cardiomyocyte hypertrophy. Remarkably, these effects on cardiac structure and function were absent in aged rodents. This could not be attributed to ineffective mobilization of bone marrow cells or decreased quantity of c-Kit ϩ cells within the myocardium with aging. However, whereas the G-CSF/SCF cocktail reduced cardiac myocyte apoptosis in old as well as in young hearts, the degree of reduction was substantially less with age and the rate of cardiomyocyte apoptosis in old animals remained high despite cytokine treatment. These findings demonstrate that G-CSF/SCF lacks therapeutic efficacy in old animals by failing to offset periinfarct apoptosis and therefore raise important concerns regarding the efficacy of novel cytokine therapies in elderly individuals at greatest risk for adverse consequences of MI.

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Activation of c‐kit is necessary for mobilization of reparative bone marrow progenitor cells in response to cardiac injury

Cited by 69 publications

References 60 publications

Cardiomyocyte-Specific Overexpression of Human Stem Cell Factor Improves Cardiac Function and Survival After Myocardial Infarction in Mice

Cardiomyocyte-Specific Overexpression of Human Stem Cell Factor Improves Cardiac Function and Survival After Myocardial Infarction in Mice

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Aging Impairs the Beneficial Effect of Granulocyte Colony-Stimulating Factor and Stem Cell Factor on Post-Myocardial Infarction Remodeling

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