Cardiac Versus Non-Cardiac Stem Cells to Repair the Heart: The Role of Autocrine/Paracrine Signals

Recent data suggest that the cardiac-restricted transcription factor GATA-4 is an anti-apoptotic factor required for adaptive responses as well as a key regulator of hypertrophy and hypertrophy-associated genes in the heart. As a leading cause of chronic heart failure, reversal of post-infarction left ventricular remodeling represents an important target for therapeutic interventions. Here we studied the role of GATA-4 as a mediator of post-infarction remodeling. Rats were subjected to experimental myocardial infarction (MI) by ligating the left anterior descending coronary artery (LAD). Ligation of the LAD decreased the DNA binding activity of GATA-4 by 69 % at day 1 after MI (P<0.001, n=7– 8) as assessed by gel mobility shift assays. At 2 weeks the GATA-4 DNA binding was significantly upregulated (2.4-fold, P<0.05, n=7), and returned to baseline at 4 weeks. To determine the functional role of GATA-4, rats underwent LAD ligation followed by peri-infarct intramyocardial delivery of adenoviral vector expressing GATA-4. Hearts treated with the GATA-4 gene transfer exhibited significantly increased ejection fraction (58±5% vs. 38±3% in LacZ-treated control animals with MI, P<0.001, n=8 –9) and fractional shortening (28±3% vs. 16±1%, P<0.001, n=8 –9) 2 weeks after MI. Accordingly, the infarct size was significantly reduced (26±4% vs. 45±4%, P<0.01, n=8 –9). To determine the cardioprotective mechanisms of GATA-4, the number of cardiac stem cells, apoptotic cardiomyocytes and capillaries were assessed. The number of capillaries (59±4/field vs. 48±3/field, P<0.051, n=7– 8) and c-kit positive stem cells (13±5 cells vs. 4±2 cells, P<0.05, n=7– 8) were increased in GATA-4 treated hearts, and a tendency to decreased apoptosis was observed in TUNEL-stained histological sections. These results indicate that the reversal of reduced GATA-4 activity prevents adverse post-infarction remodeling through increased angiogenesis, recruitment of cardiac stem cells and anti-apoptosis. GATA-4-based gene transfer may represent a novel, efficient therapeutic approach for heart failure.

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The Role of MicroRNAs in Cardiac Stem Cells

Stem Cells International ◽

10.1155/2015/194894 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Nima Purvis ◽

Andrew Bahn ◽

Rajesh Katare

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Cell Function ◽

Cardiac Stem Cells ◽

Cell Therapies ◽

Small Noncoding Rna ◽

Proliferation And Differentiation

Stem cells are considered as the next generation drug treatment in patients with cardiovascular disease who are resistant to conventional treatment. Among several stem cells used in the clinical setting, cardiac stem cells (CSCs) which reside in the myocardium and epicardium of the heart have been shown to be an effective option for the source of stem cells. In normal circumstances, CSCs primarily function as a cell store to replace the physiologically depleted cardiovascular cells, while under the diseased condition they have been shown to experimentally regenerate the diseased myocardium. In spite of their major functional role, molecular mechanisms regulating the CSCs proliferation and differentiation are still unknown. MicroRNAs (miRs) are small, noncoding RNA molecules that regulate gene expression at the posttranscriptional level. Recent studies have demonstrated the important role of miRs in regulating stem cell proliferation and differentiation, as well as other physiological and pathological processes related to stem cell function. This review summarises the current understanding of the role of miRs in CSCs. A deeper understanding of the mechanisms by which miRs regulate CSCs may lead to advances in the mode of stem cell therapies for the treatment of cardiovascular diseases.

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The role of endothelial progenitor and cardiac stem cells in the cardiovascular adaptations to age and exercise

Frontiers in Bioscience ◽

10.2741/3560 ◽

2009 ◽

Vol Volume (14) ◽

pp. 4685 ◽

Cited By ~ 22

Author(s):

Dick, H.J. Thijssen

Keyword(s):

Stem Cells ◽

Cardiac Stem Cells ◽

Endothelial Progenitor

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Ablation of MMP9 induces survival and differentiation of cardiac stem cells into cardiomyocytes in the heart of diabetics: a role of extracellular matrix

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y11-131 ◽

2012 ◽

Vol 90 (3) ◽

pp. 353-360 ◽

Cited By ~ 31

Author(s):

Paras Kumar Mishra ◽

Vishalakshi Chavali ◽

Naira Metreveli ◽

Suresh C. Tyagi

Keyword(s):

Stem Cells ◽

Extracellular Matrix ◽

Stem Cell ◽

Confocal Microscopy ◽

Cell Survival ◽

Troponin I ◽

Gelatin Zymography ◽

Cardiac Stem Cells ◽

Stem Cell Survival

The contribution of extracellular matrix (ECM) to stem cell survival and differentiation is unequivocal, and matrix metalloproteinase-9 (MMP9) induces ECM turn over; however, the role of MMP9 in the survival and differentiation of cardiac stem cells is unclear. We hypothesize that ablation of MMP9 enhances the survival and differentiation of cardiac stem cells into cardiomyocytes in diabetics. To test our hypothesis, Ins2+/− Akita, C57 BL/6J, and double knock out (DKO: Ins2+/−/MMP9−/−) mice were used. We created the DKO mice by deleting the MMP9 gene from Ins2+/−. The above 3 groups of mice were genotyped. The activity and expression of MMP9 in the 3 groups were determined by in-gel gelatin zymography, Western blotting, and confocal microscopy. To determine the role of MMP9 in ECM stiffness (fibrosis), we measured collagen deposition in the histological sections of hearts using Masson’s trichrome staining. The role of MMP9 in cardiac stem cell survival and differentiation was determined by co-immunoprecipitation (co-IP) of MMP9 with c-kit (a marker of stem cells) and measuring the level of troponin I (a marker of cardiomyocytes) by confocal microscopy in the 3 groups. Our results revealed that ablation of MMP9 (i) reduces the stiffness of ECM by decreasing collagen accumulation (fibrosis), and (ii) enhances the survival (elevated c-kit level) and differentiation of cardiac stem cells into cardiomyocytes (increased troponin I) in diabetes. We conclude that inhibition of MMP9 ameliorates stem cell survival and their differentiation into cardiomyocytes in diabetes.

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Estrogen is required for maintaining the quality of cardiac stem cells

PLoS ONE ◽

10.1371/journal.pone.0245166 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0245166

Author(s):

Al Shaimaa Hasan ◽

Lan Luo ◽

Satoko Baba ◽

Tao-Sheng Li

Keyword(s):

Stem Cells ◽

Dna Damage ◽

Potential Role ◽

Telomerase Activity ◽

Estrogen Deficiency ◽

Cardiac Stem Cells

Compared to the age-matched men, the incidence of cardiovascular diseases is lower in premenopausal but higher in postmenopausal women, suggesting the cardio-protective role of estrogen in females. Although cardiac stem cells (CSCs) express estrogen receptors, yet the effects of estrogen on CSCs remain unclear. In this study, we investigated the potential role of estrogen in maintaining the quality of CSCs by in vivo and in vitro experiments. For the in vivo study, estrogen deficiency was induced by ovariectomy in 6-weeks-old C57BL/6 female mice, and then randomly given 17β-estradiol (E2) replacements at a low dose (0.01 mg/60 days) and high dose (0.18 mg/60 days), or vehicle treatment. All mice were killed 2 months after treatments, and heart tissues were collected for ex vivo expansion of CSCs. Compared to age-matched healthy controls, estrogen deficiency slightly decreased the yield of CSCs with significantly lower telomerase activity and more DNA damage. Interestingly, E2 replacements at low and high doses significantly increased the yield of CSCs and reversed the quality impairment of CSCs following estrogen deficiency. For the in vitro study, twice-passaged CSCs from the hearts of adult healthy female mice were cultured with the supplement of 0.01, 0.1, and 1 μM E2 in the medium for 3 days. We found that E2 supplement increased c-kit expression, increased proliferative activity, improved telomerase activity, and reduced DNA damage of CSCs in a dose-dependent manner. Our data suggested the potential role of estrogen in maintaining the quality of CSCs, providing new insight into the cardio-protective effects of estrogen.

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Abstract 450: Unveiling Human Cardiac Stem Cells Role in Myocardial Ischemia-reperfusion Injury

Circulation Research ◽

10.1161/res.119.suppl_1.450 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Maria J Sebastião ◽

Margarida Serra ◽

Rute Pereira ◽

Catarina Brito ◽

Itziar Palacios ◽

...

Keyword(s):

Stem Cells ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Maturation Stage ◽

Growth Media ◽

Cardiac Stem Cells ◽

Myocardial Repair ◽

Human Donor

After an Acute Myocardial Infarction (AMI), Ischemia-Reperfusion (I/R) injury is responsible for a critical decrease in the number of viable cardiomyocytes (hCMs). Human adult myocardium harbors a population of endogenous cardiac stem cells (hCSCs) that is activated upon I/R injury, contributing to myocardial repair through the establishment of an auto/paracrine molecular crosstalk between hCSCs and hCMs in stress. Our work aims at setting up the first in vitro human I/R injury model in order to decipher the role of hCSCs and correspondent cross talk between hCSCs and hCMs upon AMI using proteomic tools. Human CSCs, hCMs cultures and co-cultures were established using human donor derived CSCs (c-kit + , CD45 - ) and hCMs derived from human induced pluripotent stem cells at different maturation stages (hiPSC-CMs). Ischemia was mimicked by substituting growth media by Ischemia Mimetic Solution (including nutrient depletion, lactate accumulation, acidosis and hyperosmosis) and placing the cells at 0% O 2 for 5 hours. In the reperfusion step, cells were placed back in their physiological culture conditions (3% O 2 ). The effect of I/R injury on growth factor secretion, cells’ viability, as well as on hCSC proliferation was accessed in both mono- and co-culture systems. In addition, hCSCs total proteome analysis was performed at different timepoints (before injury, after ischemia and after 1h and 16h of reoxygenation) by LC-MS. Important features of I/R injury were successfully captured in our model, namely hCSC proliferation activation upon insult, the increase in HGF secretion during the first hour after reoxygenation, and the protective role of hCSCs on hiPSC-CMs. The maturation stage of hiPSC-CM showed to be of high relevance in the response to injury. More than 2000 proteins were identified in hCSCs per experimental time point; proteins associated with mitochondrial dysfunction and oxidative stress response were identified in hCSCs exposed to injury. This system will allow further understanding on the molecular landscape of the myocardium during AMI, namely regarding hCSC regenerative response and hCM survival. The knowledge gained in this work will potentiate the development of novel therapies for myocardium regeneration.

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