Macrophage Subpopulations Are Essential for Infarct Repair With and Without Stem Cell Therapy

Ben-Mordechai, Tamar; Holbová, Radka; Landa‐Rouben, Natalie; Harel-Adar, Tamar; Feinberg, Micha S.; Abd‐Elrahman, Ihab; Blum, Galia; Epstein, F. H.; Silman, Zmira; Cohen, Smadar; Leor, Jonathan

doi:10.1016/j.jacc.2013.07.057

Cited by 227 publications

(227 citation statements)

References 38 publications

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“…In fact, previous studies have reported that M2 macrophages are necessary for promoting angiogenesis following MI [35,36]. Moreover, macrophages are clearly involved in the cardioprotective effect of transplanted BMSCs in mouse MI [37]. Given that transplanted W8B2 1 CRSCs did not show appreciable differentiation into cardiovascular cell types in the myocardium, direct differentiation of W8B2 1 CRSCs into a functional unit of the heart is unlikely to account for cardioprotection by this cell treatment.…”

Section: Discussionmentioning

confidence: 86%

Cardiac Repair With a Novel Population of Mesenchymal Stem Cells Resident in the Human Heart

et al. 2015

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Cardiac resident stem cells (CRSCs) hold much promise to treat heart disease but this remains a controversial field. Here, we describe a novel population of CRSCs, which are positive for W8B2 antigen and were obtained from adult human atrial appendages. W8B2 1 CRSCs exhibit a spindle-shaped morphology, are clonogenic and capable of self-renewal. W8B2 1 CRSCs show high expression of mesenchymal but not hematopoietic nor endothelial markers. W8B2 1 CRSCs expressed GATA4, HAND2, and TBX5, but not C-KIT, SCA-1, NKX2.5, PDGFRa, ISL1, or WT1. W8B2 1 CRSCs can differentiate into cardiovascular lineages and secrete a range of cytokines implicated in angiogenesis, chemotaxis, inflammation, extracellular matrix remodeling, cell growth, and survival. In vitro, conditioned medium collected from W8B2 1 CRSCs displayed prosurvival, proangiogenic, and promigratory effects on endothelial cells, superior to that of other adult stem cells tested, and additionally promoted survival and proliferation of neonatal rat cardiomyocytes. Intramyocardial transplantation of human W8B2 1 CRSCs into immunocompromised rats 1 week after myocardial infarction markedly improved cardiac function (~40% improvement in ejection fraction) and reduced fibrotic scar tissue 4 weeks after infarction. Hearts treated with W8B2 1 CRSCs showed less adverse remodeling of the left ventricle, a greater number of proliferating cardiomyocytes (Ki67 1 cTnT 1 cells) in the remote region, higher myocardial vascular density, and greater infiltration of CD163 1 cells (a marker for M2 macrophages) into the border zone and scar regions. In summary, W8B2 1 CRSCs are distinct from currently known CRSCs found in human hearts, and as such may be an ideal cell source to repair myocardial damage after infarction. STEM CELLS 2015;33:3100-3113 SIGNIFICANCE STATEMENTWe have isolated a new type of adult stem cell from human heart tissue, which carries markers different from known cardiac resident stem cells. These cells can be rapidly expanded and have powerful regenerative effects when injected into the hearts of rats after heart attack, such that they greatly improve cardiac performance compared with controls that have also suffered heart attack. We showed these cells protect other cells from dying and promote growth of blood vessels, actions which assist cardiac regeneration. Importantly, their protective actions in this regard are superior to those of other adult stem cells that have shown some benefit in clinical trials after heart attack. These new stem cells have great potential for repairing the heart, and could be derived from the individual patients in need, avoiding any problem of immunorejection.

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Section: Discussionmentioning

confidence: 86%

Cardiac Repair With a Novel Population of Mesenchymal Stem Cells Resident in the Human Heart

et al. 2015

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“…Both reports propose that modulation of epicardial paracrine environment is potentially key for the observed enhanced myocardial repair (Huang et al, 2012;Zhou et al, 2011), underscoring the potentially important role of cTMs and exogenous macrophages in regulating the post-MI inflammatory milieu and tissue repair. The finding that macrophage signalling, particularly from M2-like macrophages, enhances MSC survival, engraftment and potentially also differentiation (Ben-Mordechai et al, 2013;Freytes et al, 2013), suggests that the role of macrophage signalling may be also important for the regulation of epicardial progenitor cells to repair the damaged myocardium.…”

Section: Macrophages and Regulation Of Epicardial Progenitorsmentioning

confidence: 99%

Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation

2014

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Macrophages are an immune cell type found in every organ of the body. Classically, macrophages are recognised as housekeeping cells involved in the detection of foreign antigens and danger signatures, and the clearance of tissue debris. However, macrophages are increasingly recognised as a highly versatile cell type with a diverse range of functions that are important for tissue homeostasis and injury responses. Recent research findings suggest that macrophages contribute to tissue regeneration and may play a role in the activation and mobilisation of stem cells. This review describes recent advances in our understanding of the role played by macrophages in cardiac tissue maintenance and repair following injury. We examine the involvement of exogenous and resident tissue macrophages in cardiac inflammatory responses and their potential activity in regulating cardiac regeneration.

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“…A relatively high amount of two pro-inflammatory mediators, MCP-1/CCL2 and IL-1b, are also expressed by MGs on MSC coculture. We can only speculate that due to the fact that mononuclear phagocytes with various phenotypic polarization are crucial for tissue repair and regeneration [47,48], the MCP-1/CCL2-induced microglia accumulation at the site of tissue injury or inflammation could have a beneficial effect on the repair process. On the other hand, the IL-1b secretion by MGs in the presence of stem cells is consistent with an earlier report [35] and could be explained by two facts.…”

Section: Microglia Activation and Effector Functionsmentioning

confidence: 99%

Regulation of Mouse Microglia Activation and Effector Functions by Bone Marrow-Derived Mesenchymal Stem Cells

Hegyi

Környei

Ferenczi

et al. 2014

Stem Cells and Development

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Macrophage Subpopulations Are Essential for Infarct Repair With and Without Stem Cell Therapy

Abstract: Some of the protective effects of MSCs on infarct repair are mediated by macrophages, which are essential for early healing and repair. Thus, targeting macrophages could be a novel strategy to improve infarct healing and repair.

Cited by 227 publications

References 38 publications

Cardiac Repair With a Novel Population of Mesenchymal Stem Cells Resident in the Human Heart

Cardiac Repair With a Novel Population of Mesenchymal Stem Cells Resident in the Human Heart

Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation

Regulation of Mouse Microglia Activation and Effector Functions by Bone Marrow-Derived Mesenchymal Stem Cells

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