3D-model of adult cardiac stem cells promotes cardiac differentiation and resistance to oxidative stress

Abstract A growing amount of data indicates that the heart harbours stem cells (CSCs) with regenerative potential, however the origin(s) of adult CSCs is still unknown. The expression of Kit a marker of several stem cell types, including hematopoietic and cardiac stem cells, suggests that Kit positive-CSCs may derive, at least in part, from extracardiac sources. In addition, it has been suggested that bone marrow (BM) cells may be mobilized, home into the heart and trans-differentiate into cardiomyocytes, following myocardial infarction. To investigate whether BM cells can contribute to repopulate the cardiac Kit+ stem cell pool, we transplanted BM cells from a mouse line expressing transgenic Green Fluorescent Protein (GFP) under the control of Kit regulatory elements, into wild type irradiated recipients. After hematological reconstution (4–5 months) and following cardiac infarction, cardiac cells were grown in vitro into typical “cardiospheres” (Messina et al., Circ. Res. 95,911;2004). The cardiospheres obtained, although not numerous, were all GFP fluorescent; this result was confirmed by PCR analysis of genomic DNA of individual CSs. At confocal microscopy, cells at the periphery of CSs showed coexistence of low GFP with cardiac markers, such as Troponin I and the transcription factor NKx2.5, consistent with the expected kit downregulation during cardiac differentiation. Our results show that cells of bone marrow origin can give rise, after homing into the heart, to cells with properties of Kit+ CSC. In contrast, CSCs isolated from kit/GFP transgenic mice are not able, upon transplantation, to repopulate the bone marrow of wild-type irradiated recipients. Thus, at least in pathological conditions, part of the Kit-positive CSCs population may be generated by BM-derived cells, capable of adopting in the heart the same function and features of cardiac stem cells.

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Abstract 52: Impaired Ephrin A1/EphA2 Signaling Results in Defective Migration and Homing of Senescent Human Cardiac Stem Cells

Circulation Research ◽

10.1161/res.111.suppl_1.a52 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Ramaswamy Kannappan ◽

Yingnan Bai ◽

Sergio Signore ◽

Maria Cimini ◽

Joao Ferreira-Martins ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Fold Increase ◽

Cardiac Stem Cells ◽

Ventricular Performance ◽

Post Translational Modifications ◽

Caveolin 1 ◽

Molecular Alterations ◽

Injured Area ◽

Pre Treatment

Aging is the major independent risk factor for chronic heart failure. Despite the presence of cardiac stem cells (CSCs), the old human heart undergoes progressive deterioration in ventricular performance, coupled with scattered foci of fibrosis and accumulation of poorly contracting myocytes. We raised the possibility that defects in the translocation of senescent human CSCs (hCSCs) to the sites of damage constitute a key determinant in the manifestation of the aging myopathy. We report that ephrin A1-EphA2 receptor signaling is a critical modulator of hCSC motility. Ephrin A1, a membrane-anchored protein, is expressed on the myocyte sarcolemma and acts as a ligand for the EphA2 receptor on neighboring hCSCs, facilitating their migration. Pre-treatment of young hCSCs with ephrin A1 resulted in enhanced movement of the transplanted cells to the necrotic tissue, with formation of new myocardium and improvement in cardiac function. Whether senescent hCSCs promote a comparable regenerative response remained to be established. Surprisingly, the expression of EphA2 did not differ in young and old hCSCs. With respect to young cells, senescent hCSCs showed a 2-fold increase in intracellular ROS levels. Oxidative stress led to post-translational modifications and functional alterations of the EphA2 receptor. Specifically, the ability of ephrin A1 to induce phosphorylation of the EphA2 receptor was markedly attenuated in senescent hCSCs, resulting in inadequate activation of Src family proteins. As a consequence, the phosphorylation and activity of caveolin-1, a substrate of Src kinases, was reduced. These molecular alterations led to impaired endocytosis of the ligand-receptor complex, a cellular process essential for ephrin A1-EphA2 signaling. Lack of endocytosis precluded rearrangement of the actin cytoskeleton and cell migration. Importantly, ephrin A1-stimulated senescent hCSCs delivered to infarcted rats accumulated in proximity of the site of injection and did not translocate to the ischemic area. Thus, oxidative stress interferes with EphA2 signaling in aging hCSCs, negatively affecting their migration. Restoration of the EphA2 function in old hCSCs may enhance their mobilization and improve cell targeting to the injured area.

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Novel preparation of Au nanoparticles loaded Laponite nanoparticles/ECM injectable hydrogel on cardiac differentiation of resident cardiac stem cells to cardiomyocytes

Journal of Photochemistry and Photobiology B Biology ◽

10.1016/j.jphotobiol.2018.12.022 ◽

2019 ◽

Vol 192 ◽

pp. 49-54 ◽

Cited By ~ 13

Author(s):

Youjian Zhang ◽

Weidong Fan ◽

Kuihua Wang ◽

Huina Wei ◽

Ruicheng Zhang ◽

...

Keyword(s):

Stem Cells ◽

Au Nanoparticles ◽

Cardiac Differentiation ◽

Cardiac Stem Cells ◽

Injectable Hydrogel

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Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1α/Jagged1/Notch1 signaling

Acta Pharmaceutica Sinica B ◽

10.1016/j.apsb.2018.06.003 ◽

2018 ◽

Vol 8 (5) ◽

pp. 795-804 ◽

Cited By ~ 7

Author(s):

Keke Wang ◽

Ranran Ding ◽

Yanping Ha ◽

Yanan Jia ◽

Xiaomin Liao ◽

...

Keyword(s):

Stem Cells ◽

Cardiac Differentiation ◽

Cardiac Stem Cells ◽

Notch1 Signaling

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Exosomes Derived from miR-214-Enriched Bone Marrow-Derived Mesenchymal Stem Cells Regulate Oxidative Damage in Cardiac Stem Cells by Targeting CaMKII

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4971261 ◽

2018 ◽

Vol 2018 ◽

pp. 1-21 ◽

Cited By ~ 22

Author(s):

Yan Wang ◽

Ranzun Zhao ◽

Debin Liu ◽

Wenwen Deng ◽

Guanxue Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Oxidative Damage ◽

Bioactive Molecules ◽

Cardiac Stem Cells ◽

Stress Injury ◽

Hypoxic Conditions ◽

Oxidative Stress Injury

Cardiac stem cells (CSCs) have emerged as one of the most promising stem cells for cardiac protection. Recently, exosomes from bone marrow-derived mesenchymal stem cells (BMSCs) have been found to facilitate cell proliferation and survival by transporting various bioactive molecules, including microRNAs (miRs). In this study, we found that BMSC-derived exosomes (BMSC-exos) significantly decreased apoptosis rates and reactive oxygen species (ROS) production in CSCs after oxidative stress injury. Moreover, a stronger effect was induced by exosomes collected from BMSCs cultured under hypoxic conditions (Hypoxic-exos) than those collected from BMSCs cultured under normal conditions (Nor-exos). We also observed greater miR-214 enrichment in Hypoxic-exos than in Nor-exos. In addition, a miR-214 inhibitor or mimics added to modulate miR-214 levels in BMSC-exos revealed that exosomes from miR-214-depleted BMSCs partially reversed the effects of hypoxia-induced exosomes on oxidative damage in CSCs. These data further confirmed that miR-214 is the main effector molecule in BMSC-exos that protects CSCs from oxidative damage. miR-214 mimic and inhibitor transfection assays verified that CaMKII is a target gene of miR-214 in CSCs, with exosome-pretreated CSCs exhibiting increased miR-214 levels but decreased CaMKII levels. Therefore, the miR-214/CaMKII axis regulates oxidative stress-related injury in CSCs, such as apoptosis, calcium homeostasis disequilibrium, and excessive ROS accumulation. Collectively, these findings suggest that BMSCs release miR-214-containing exosomes to suppress oxidative stress injury in CSCs through CaMKII silencing.

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