scholarly journals Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1894 ◽  
Author(s):  
Stephanie W. Tobin ◽  
Faisal J. Alibhai ◽  
Richard D. Weisel ◽  
Ren-Ke Li
Keyword(s):  
Myocardial Infarction ◽  
Immune System ◽  
Immune Cell ◽  
Heart Function ◽  
Cardiac Repair ◽  
Cell Aging ◽  
Cell Behavior ◽  
Complex Nature ◽  
Older Individuals ◽  
Hematopoietic Stem

The importance of the immune system for cardiac repair following myocardial infarction is undeniable; however, the complex nature of immune cell behavior has limited the ability to develop effective therapeutics. This limitation highlights the need for a better understanding of the function of each immune cell population during the inflammatory and resolution phases of cardiac repair. The development of reliable therapies is further complicated by aging, which is associated with a decline in cell and organ function and the onset of cardiovascular and immunological diseases. Aging of the immune system has important consequences on heart function as both chronic cardiac inflammation and an impaired immune response to cardiac injury are observed in older individuals. Several studies have suggested that rejuvenating the aged immune system may be a valid therapeutic candidate to prevent or treat heart disease. Here, we review the basic patterns of immune cell behavior after myocardial infarction and discuss the autonomous and nonautonomous manners of hematopoietic stem cell and immune cell aging. Lastly, we identify prospective therapies that may rejuvenate the aged immune system to improve heart function such as anti-inflammatory and senolytic therapies, bone marrow transplant, niche remodeling and regulation of immune cell differentiation.

Abstract 197: Plasminogen Is Required for Hematopoietic Stem Cell-Mediated Cardiac Repair After Myocardial Infarction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yanqing Gong ◽  
Ying Li ◽  
Jane Hoover-Plow
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Stem Cell ◽  
Heart Function ◽  
Critical Role ◽  
The United States ◽  
Cardiac Repair ◽  
Internal Diameter ◽  
Hematopoietic Stem

Myocardial infarction (MI) is the primary cause of death throughout the United States. Granulocyte colony-stimulating factor (G-CSF) is used to mobilize hematopoietic progenitor and stem cells (HPSC) to improve cardiac recovery after MI. However, poor-mobilization to G-CSF is observed in 25% of patients and 10-20% of healthy donors. Therefore, a better understanding of the underlying mechanisms may offer novel approaches for G-CSF-mediated therapeutics. Our previous studies have identified an essential role of Plg in HPSC mobilization from bone marrow (BM) in response to G-CSF. Here, we investigate the role of Plg in G-CSF-stimulated cardiac repair after MI. Our data show that G-CSF significantly improves cardiac repair including increasing neovascularization in the infarct area, and improving ejection fraction and LV internal diameter determined by echocardiogram in WT mice. No improvement on heart function is observed in Plg -/- mice, indicating Plg is required for G-CSF-regulated cardiac repair after MI. To investigate whether Plg regulates HPSC recruitment to the ischemic area, BM transplantation with EGFP-expressing BM cells was performed to visualize BM-derived stem cells in infarcted tissue. Our data show that G-CSF dramatically increases recruitment of GFP + cKit + cells (by 12 fold) in WT mice but not in Plg -/- mice. In addition, BM stem cell-derived vessels and arteries are infrequent in Plg -/- mice suggesting that Plg enhances cardiac repair by promoting stem cell recruitment to the lesion. In further studies, we investigated the role of Plg in the regulation of SDF-1/CXCR-4 axis, a major regulator for HPSC recruitment. Our results show that G-CSF significantly increases CXCR-4 expression in the infarcted area in WT mice. While G-CSF-induced CXCR-4 expression is markedly decreased (80%) in Plg -/- mice, suggesting Plg may regulate CXCR-4 expression during HSPC recruitment to injured heart. Interestingly, Plg does not affect SDF-1 expression in response to G-CSF treatment. Taken together, our findings have identified a critical role of Plg in HSPC recruitment to the lesion site and subsequent tissue repair after MI. Thus, targeting Plg may offer a new therapeutic strategy to improve G-CSF-mediated cardiac repair after MI.

Abstract 13: Plasminogen Is Required for Hematopoietic Stem Cell-Mediated Cardiac Repair After Myocardial Infarction

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Yanqing Gong ◽  
Jane Hoover-Plow ◽  
Ying Li
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Tissue Repair ◽  
Critical Role ◽  
Cardiac Repair ◽  
Internal Diameter ◽  
Hematopoietic Stem

Ischemic heart disease, including myocardial infarction (MI), is the primary cause of death throughout the US. Granulocyte colony-stimulating factor (G-CSF) is used to mobilize hematopoietic progenitor and stem cells (HPSC) to improve cardiac recovery after MI. However, poor-mobilization to G-CSF is observed in 25% of patients and 10-20% of healthy donors. Therefore, a better understanding of the underlying mechanisms regulating G-CSF-induced cardiac repair may offer novel approaches for strengthening stem cell-mediated therapeutics. Our previous studies have identified an essential role of Plg in HPSC mobilization from bone marrow (BM) in response to G-CSF. Here, we investigate the role of Plg in G-CSF-stimulated cardiac repair after MI. Our data show that G-CSF significantly improves cardiac tissue repair including increasing neovascularization in the infarct area, and improving ejection fraction and LV internal diameter by echocardiogram in wild-type mice. No improvement in tissue repair and heart function by G-CSF is observed in Plg -/- mice, indicating that Plg is required for G-CSF-regulated cardiac repair after MI. To investigate whether Plg regulates HPSC recruitment to ischemia area, bone marrow transplantion (BMT) with EGFP-expressing BM cells was performed to visualize BM-derived stem cells in infarcted tissue. Our data show that G-CSF dramatically increases recruitment of GFP+ cells (by 16 fold) in WT mice but not in Plg -/- mice, suggesting that Plg is essential for HPSC recruitment from BM to the lesion sites after MI. In further studies, we investigated the role of Plg in the regulation of SDF-1/CXCR-4 axis, a major regulator for HPSC recruitment. Our results show that G-CSF significantly increases CXCR-4 expression in infarcted area in WT mice. While G-CSF-induced CXCR-4 expression is markedly decreased (80%) in Plg -/- mice, suggesting Plg may regulate CXCR-4 expression during HSPC recruitment to injured heart. Interestingly, Plg does not affect SDF-1 expression in response to G-CSF treatment. Taken together, our findings have identified a critical role of Plg in HSPC recruitment to the lesion site and subsequent tissue repair after MI. Thus, targeting Plg may offer a new therapeutic strategy to improve G-CSF-mediated cardiac repair after MI.

EZH2 function in immune cell development

2020 ◽  
Vol 401 (8) ◽  
pp. 933-943 ◽  
Author(s):  
Stephen L. Nutt ◽  
Christine Keenan ◽  
Michaël Chopin ◽  
Rhys S. Allan
Keyword(s):  
Immune System ◽  
Cell Function ◽  
Immune Cell ◽  
Proliferating Cells ◽  
Hematopoietic Stem ◽  
Polycomb Repressive Complex 2 ◽  
Current State ◽  
Core Components ◽  
And Function ◽  
Cell Cycle Inhibitors

AbstractThe polycomb repressive complex 2 (PRC2) consists of three core components EZH2, SUZ12 and EED. EZH2 catalyzes the methylation of lysine 27 of histone H3, a modification associated with gene silencing. Through gene duplication higher vertebrate genomes also encode a second partially redundant methyltransferase, EZH1. Within the mammalian immune system most research has concentrated on EZH2 which is expressed predominantly in proliferating cells. EZH2 and other PRC2 components are required for hematopoietic stem cell function and lymphocyte development, at least in part by repressing cell cycle inhibitors. At later stages of immune cell differentiation, EZH2 plays essential roles in humoral and cell-mediated adaptive immunity, as well as the maintenance of immune homeostasis. EZH2 is often overactive in cancers, through both gain-of-function mutations and over-expression, an observation that has led to the development and clinical testing of specific EZH2 inhibitors. Such inhibitors may also be of use in inflammatory and autoimmune settings, as EZH2 inhibition dampens the immune response. Here, we will review the current state of understanding of the roles for EZH2, and PRC2 more generally, in the development and function of the immune system.

scholarly journals P2Y12 antagonists and cardiac repair post-myocardial infarction: global and regional heart function analysis and molecular assessments in pigs

2018 ◽  
Vol 114 (14) ◽  
pp. 1860-1870 ◽  
Author(s):  
Gemma Vilahur ◽  
Manuel Gutiérrez ◽  
Laura Casani ◽  
Carmen Lambert ◽  
Guiomar Mendieta ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Function Analysis ◽  
Heart Function ◽  
Cardiac Repair ◽  
Post Myocardial Infarction ◽  
P2y12 Antagonists

scholarly journals Causes and Mechanisms of Hematopoietic Stem Cell Aging

2019 ◽  
Vol 20 (6) ◽  
pp. 1272 ◽  
Author(s):  
Jungwoon Lee ◽  
Suk Yoon ◽  
Inpyo Choi ◽  
Haiyoung Jung
Keyword(s):  
Immune System ◽  
Molecular Mechanisms ◽  
The Elderly ◽  
Cell Aging ◽  
Extrinsic Factors ◽  
Hematopoietic Stem ◽  
Age Related ◽  
Stem Cell Aging ◽  
Related Stress

Many elderly people suffer from hematological diseases known to be highly age-dependent. Hematopoietic stem cells (HSCs) maintain the immune system by producing all blood cells throughout the lifetime of an organism. Recent reports have suggested that HSCs are susceptible to age-related stress and gradually lose their self-renewal and regeneration capacity with aging. HSC aging is driven by cell-intrinsic and -extrinsic factors that result in the disruption of the immune system. Thus, the study of HSC aging is important to our understanding of age-related immune diseases and can also provide potential strategies to improve quality of life in the elderly. In this review, we delineate our understanding of the phenotypes, causes, and molecular mechanisms involved in HSC aging.

scholarly journals Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 141 (11) ◽  
pp. 916-930 ◽  
Author(s):  
Yoav Hadas ◽  
Adam S. Vincek ◽  
Elias Youssef ◽  
Magdalena M. Żak ◽  
Elena Chepurko ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Left Ventricle ◽  
Cell Survival ◽  
Immune Cell ◽  
De Novo ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Sphingolipid Metabolism ◽  
Death Rates

Background: Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI. Methods: We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI. Results: We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils. Conclusions: Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.

CXCR4+ CD45− Tissue-Committed Stem Cells (TCSC) for Myocardium Reside in the Bone Marrow, Are Mobilized into the Peripheral Blood during Myocardial Infarction, and “Home” to Infarcted Myocardium in CXCR4-SDF-1 and HGF/SF-c-Met Dependent Manner.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2131-2131
Author(s):  
Magda Kucia ◽  
Buddhadeb Dawn ◽  
Yiru Guo ◽  
Greg Hunt ◽  
Marcin Wysoczynski ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
Cardiac Differentiation ◽  
Specific Cell ◽  
Dependent Manner ◽  
Older Individuals ◽  
Hematopoietic Stem ◽  
Infarcted Myocardium

Abstract Several recent studies in animals as well as humans support the notion that bone marrow (BM)-derived cells participate in myocardial regeneration. However, this subject remains highly controversial and the identity of the specific cell type responsible for regeneration remains unknown. Recent work from our laboratory revealed that BM contains a highly mobile population of CXCR4+ cells that express mRNA for various markers of early tissue-committed stem cells (TCSC) and which are distinct from hematopoietic stem cells (HSC) (Leukemia2004:18;29–40). In the current study we investigated whether BM also contains a mobile pool of TCSC destined to differentiate into cardiomyocytes. Our data demonstrate that TCSC for cardiomyocytes (i) are present in significant amounts in BM harvested from young (1–2 month-old) while being barely detectable in older (1-year-old) mice; ii) reside in populations of murine BM-derived non-hematopoietic Sca-1+ CD45− cells and in population of human CXCR4+ CD34+ AC133+ CD45− BMMNC, iii) are mobilized from BM into peripheral blood (PB) during pharmacological mobilization or myocardial infarction; iv) the identified by us chemoattractants for these cells: stromal derived factor -1 (SDF-1), and hepatocyte growth factor/scatter factor (HGF/SF) are upregulated in infarcted myocardium, and v) blocking experiments with T140 (CXCR4 antagonist) and K252a (c-MET antagonist) confirmed that TCSC for cardiomyocytes are chemoattracted to the damaged myocardium in SDF-1-CXCR4 and SF/HGF-c-Met dependent manner. Thus, we conclude that the bone marrow is a potential source of TCSC for heart repair and since purified CD45+ HSC neither express cardiac markers nor differentiate in vitro into cardiomyocytes, we provide for the first time evidence that cardiac TCSC residing in bone marrow but not “plastic” HSC may account for cardiac differentiation of BM-derived cells. These observations provide rationale for further studies aimed at optimizing therapeutic cardiac regeneration by BM-derived non-hematopoietic cardiac TCSC. Finally, our observation that the number of marrow derived mobile/circulating cardiac TCSC is the highest in BM of young animals and decreases with age provides a novel insight into aging and may explain why the heart regeneration process becomes less effective in older individuals.

scholarly journals Immunosenescence in Testicular Cancer Survivors: Potential Implications of Cancer Therapies and Psychological Distress

2021 ◽  
Vol 10 ◽  
Author(s):  
Silvia De Padova ◽  
Milena Urbini ◽  
Giuseppe Schepisi ◽  
Alessandra Virga ◽  
Elena Meggiolaro ◽  
...  
Keyword(s):  
Immune System ◽  
Testicular Cancer ◽  
Psychological Stress ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
T Cell Response ◽  
Premature Aging ◽  
High Dose ◽  
Hematopoietic Stem

Testicular cancer (TC) is the most frequent solid tumor diagnosed in young adult males. Although it is a curable tumor, it is frequently associated with considerable short-term and long-term morbidity. Both biological and psychological stress experienced during cancer therapy may be responsible for stimulating molecular processes that induce premature aging and deterioration of immune system (immunosenescence) in TC survivors, leading to an increased susceptibility to infections, cancer, and autoimmune diseases. Immunosenescence is a remodeling of immune cell populations with inversion of the CD4:CD8 ratio, accumulation of highly differentiated memory cells, shrinkage of telomeres, shift of T-cell response to Th2 type, and release of pro-inflammatory signals. TC survivors exposed to chemotherapy show features of immunological aging, including an increase in memory T-cells (CD4+ and CD8+) and high expression of the senescence biomarker p16INK4a in CD3+ lymphocytes. However, the plethora of factors involved in the premature aging of TC survivors make the situation more complex if we also take into account the psychological stress and hormonal changes experienced by patients, as well as the high-dose chemotherapy and hematopoietic stem cell transplantation that some individuals may be required to undergo. The relatively young age and the long life expectancy of TC patients bear witness to the importance of improving quality of life and of alleviating long-term side-effects of cancer treatments. Within this context, the present review takes an in-depth look at the molecular mechanisms of immunosenescence, describing experimental evidence of cancer survivor aging and highlighting the interconnected relationship between the many factors modulating the aging of the immune system of TC survivors.

scholarly journals Immunopharmacology of Post-Myocardial Infarction and Heart Failure Medications

2018 ◽  
Vol 7 (11) ◽  
pp. 403 ◽  
Author(s):  
Mona Panahi ◽  
Nimai Vadgama ◽  
Mathun Kuganesan ◽  
Fu Ng ◽  
Susanne Sattler
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Immune Response ◽  
Immune System ◽  
Tissue Damage ◽  
Heart Function ◽  
The Body ◽  
Inflammatory Conditions ◽  
Drug Classes ◽  
Potential Benefits

The immune system responds to acute tissue damage after myocardial infarction (MI) and orchestrates healing and recovery of the heart. However, excessive inflammation may lead to additional tissue damage and fibrosis and exacerbate subsequent functional impairment, leading to heart failure. The appreciation of the immune system as a crucial factor after MI has led to a surge of clinical trials investigating the potential benefits of immunomodulatory agents previously used in hyper-inflammatory conditions, such as autoimmune disease. While the major goal of routine post-MI pharmacotherapy is to support heart function by ensuring appropriate blood pressure and cardiac output to meet the demands of the body, several drug classes also affect a range of immunological pathways and modulate the post-MI immune response, which is crucial to take into account when designing future immunomodulatory trials. This review outlines how routine post-MI pharmacotherapy affects the immune response and may thus influence post-MI outcomes and development towards heart failure. Current key drug classes are discussed, including platelet inhibitors, statins, β-blockers, and renin–angiotensin–aldosterone inhibitors.

scholarly journals Role of Endogenous Glucocorticoids in Cancer in the Elderly

2018 ◽  
Vol 19 (12) ◽  
pp. 3774 ◽  
Author(s):  
Emira Ayroldi ◽  
Lorenza Cannarile ◽  
Sabrina Adorisio ◽  
Domenico Delfino ◽  
Carlo Riccardi
Keyword(s):  
Immune System ◽  
Chronic Stress ◽  
Immune Cell ◽  
The Elderly ◽  
Cellular Level ◽  
Cellular Aging ◽  
Cell Aging ◽  
Cell Mediated Immunity ◽  
Epigenetic Alterations ◽  
Thymic Involution

Although not a disease itself, aging represents a risk factor for many aging-related illnesses, including cancer. Numerous causes underlie the increased incidence of malignancies in the elderly, for example, genomic instability and epigenetic alterations that occur at cellular level, which also involve the immune cells. The progressive decline of the immune system functions that occurs in aging defines immunosenescence, and includes both innate and adaptive immunity; the latter undergoes major alterations. Aging and chronic stress share the abnormal hypothalamic–pituitary–adrenal axis activation, where altered peripheral glucocorticoids (GC) levels and chronic stress have been associated with accelerated cellular aging, premature immunosenescence, and aging-related diseases. Consequently, changes in GC levels and sensitivity contribute to the signs of immunosenescence, namely fewer naïve T cells, poor immune response to new antigens, decreased cell-mediated immunity, and thymic involution. GC signaling alterations also involve epigenetic alterations in DNA methylation, with transcription modifications that may contribute to immunosenescence. Immune cell aging leads to decreased levels of immunosurveillance, thereby providing tumor cells one more route for immune system escape. Here, the contribution of GC secretion and signaling dysregulation to the increased incidence of tumorigenesis in the elderly is reviewed.

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