Abstract 018: Rat Ckit+ Cardiac Progenitor Cells Release Pro-survival Micrornas In Exosomes Following Hypoxic Stimulation.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Warren D Gray ◽  
Nnenna Finn ◽  
Charles Searles ◽  
Michael E Davis
Keyword(s):  
Progenitor Cells ◽  
Cell Types ◽  
Cardiac Progenitor Cells ◽  
Protective Effects ◽  
Mrna Targets ◽  
Hypoxic Conditions ◽  
Infarcted Heart ◽  
Developed Nations ◽  
Future Work ◽  
Infarcted Region

Introduction: Cardiovascular disease is the leading cause of morbidity and mortality among developed nations, and acute myocardial infarction is the major subgroup. The need exists for cardiac therapeutic systems that mitigate tissue damage and induce regeneration within and around the infarcted region. Cardiac progenitor cells (CPCs) and other stem cell types have been attractive candidates for therapies. However, results suggest that regenerative or protective effects may occur through paracrine mechanisms. One such way may be through cell-cell transfer of microRNA (miR) via cell-secreted exosomes, which contain protein, mRNA, and miR. Cell-based therapies face substantial limitations, and therapies avoid these limitations and mimic paracrine efforts—such as delivery of harvested exosomes—have yet to be developed due in part to lack of characterization. Hypothesis: We hypothesized that in response to hypoxic conditions, CPCs secrete a pro-regenerative miRnome within exosomes. Methods: We used an Affymetrix MicroRNA GeneChip microarray to identify the miR populations that were present in CPC-conditioned media after hypoxic and normoxic treatments. Exosomes were isolated via ultracentrifugation (100,000xG) and validated by anti-CD9 immunohistochemistry and dynamic light scattering. We used RT-qPCR to quantify levels of miR upregulation in secreted exosomes. Results: We found seven miRs upregulated (1.3- to 7.9-fold) due to hypoxia stimulation. Within that miRnome, two miRs ([[Unable to Display Character: ‐]]20a, [[Unable to Display Character: ‐]]210) are known to exert cardioprotection in infarct models, providing evidence of a potential beneficial paracrine effect from CPCs. Four of the remaining miRs (-15b, -17, -103, -199a) have been shown to regulate angiogenesis, proliferation, apoptosis, and fibrosis in various cell and tissue types. One miR ([[Unable to Display Character: ‐]]292) has been largely unexplored, but predicted mRNA targets include CTGF, which is involved in cell adhesion and fibrosis. Conclusions: The strong evidence of anti-apoptotic and anti-fibrotic potential of this miRnome indicates that the cocktail may serve as a powerful modulator of cardiac remodeling. Future work will investigate applying miR-containing exosomes from hypoxia-stimulated CPCs as a therapy to rescue the infarcted heart.

EPO and EPO-Receptor System as Potential Actionable Mechanism for the Protection of Brain and Heart in Refractory Epilepsy and SUDEP

2020 ◽  
Vol 26 (12) ◽  
pp. 1356-1364 ◽  
Author(s):  
Jerónimo Auzmendi ◽  
María B. Puchulu ◽  
Julio C. G. Rodríguez ◽  
Ana M. Balaszczuk ◽  
Alberto Lazarowski ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Wide Spectrum ◽  
Cell Types ◽  
Heart Tissue ◽  
Erythropoietin Receptor ◽  
Protective Effects ◽  
Receptor System ◽  
Erythroid Progenitor ◽  
Neuronal Populations ◽  
Hypoxic Conditions

The most important activity of erythropoietin (EPO) is the regulation of erythrocyte production by activation of the erythropoietin receptor (EPO-R), which triggers the activation of anti-apoptotic and proliferative responses of erythroid progenitor cells. Additionally, to erythropoietic EPO activity, an antiapoptotic effect has been described in a wide spectrum of tissues. EPO low levels are found in the central nervous system (CNS), while EPO-R is expressed in most CNS cell types. In spite of EPO-R high levels expressed during the hypoxicischemic brain, insufficient production of endogenous cerebral EPO could be the cause of determined circuit alterations that lead to the loss of specific neuronal populations. In the heart, high EPO-R expression in cardiac progenitor cells appears to contribute to myocardial regeneration under EPO stimulation. Several lines of evidence have linked EPO to an antiapoptotic role in CNS and in heart tissue. In this review, an antiapoptotic role of EPO/EPO-R system in both brain and heart under hypoxic conditions, such as epilepsy and sudden death (SUDEP) has been resumed. Additionally, their protective effects could be a new field of research and a novel therapeutic strategy for the early treatment of these conditions and avoid SUDEP.

scholarly journals Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

2016 ◽  
Vol 310 (11) ◽  
pp. H1622-H1648 ◽  
Author(s):  
Monia Savi ◽  
Leonardo Bocchi ◽  
Stefano Rossi ◽  
Caterina Frati ◽  
Gallia Graiani ◽  
...  
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Connexin 43 ◽  
Cardiac Progenitor Cells ◽  
Antiarrhythmic Action ◽  
Mechanical Function ◽  
Electrical Stability ◽  
Intramyocardial Injection ◽  
Infarcted Heart ◽  
Connexin 40

c-Kitpos cardiac progenitor cells (CPCs) represent a successful approach in healing the infarcted heart and rescuing its mechanical function, but electrophysiological consequences are uncertain. CPC mobilization promoted by hepatocyte growth factor (HGF) and IGF-1 improved electrogenesis in myocardial infarction (MI). We hypothesized that locally delivered CPCs supplemented with HGF + IGF-1 (GFs) can concur in ameliorating electrical stability of the regenerated heart. Adult male Wistar rats (139 rats) with 4-wk-old MI or sham conditions were randomized to receive intramyocardial injection of GFs, CPCs, CPCs + GFs, or vehicle (V). Enhanced green fluorescent protein-tagged CPCs were used for cell tracking. Vulnerability to stress-induced arrhythmia was assessed by telemetry-ECG. Basic cardiac electrophysiological properties were examined by epicardial multiple-lead recording. Hemodynamic function was measured invasively. Hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. Compared with V and at variance with individual CPCs, CPCs + GFs approximately halved arrhythmias in all animals, restoring cardiac anisotropy toward sham values. GFs alone reduced arrhythmias by less than CPCs + GFs, prolonging ventricular refractoriness without affecting conduction velocity. Concomitantly, CPCs + GFs reactivated the expression levels of Connexin-43 and Connexin-40 as well as channel proteins of key depolarizing and repolarizing ion currents differently than sole GFs. Mechanical function and anatomical remodeling were equally improved by all regenerative treatments, thus exhibiting a divergent behavior relative to electrical aspects. Conclusively, we provided evidence of distinctive antiarrhythmic action of locally injected GF-supplemented CPCs, likely attributable to retrieval of Connexin-43, Connexin-40, and Cav1.2 expression, favoring intercellular coupling and spread of excitation in mended heart.

Evidence of synergistic/additive effects of sildenafil and erythropoietin in enhancing survival and migration of hypoxic endothelial cells

2013 ◽  
Vol 304 (4) ◽  
pp. L230-L239 ◽  
Author(s):  
Elena Gammella ◽  
Caroline Leuenberger ◽  
Max Gassmann ◽  
Louise Ostergaard
Keyword(s):  
Endothelial Cells ◽  
Combination Treatment ◽  
Synergistic Effects ◽  
Annexin V ◽  
Cell Types ◽  
Blue Staining ◽  
Protective Effects ◽  
Hypoxic Conditions ◽  
Phosphodiesterase Type 5 Inhibitor ◽  
And Migration

Endothelial cell dysfunction is a common event to several pathologies including pulmonary hypertension, which is often associated with hypoxia. As the endothelium plays an essential role in regulating the dynamic interaction between pulmonary vasodilatation and vasoconstriction, this cell type is fundamental in the development of vascular remodeling and increased vascular resistance. We investigated the protective effects of sildenafil, a phosphodiesterase type 5 inhibitor, given in combination with erythropoietin (Epo), as it has been demonstrated that both drugs have antiapoptotic effects on several cell types. Specifically, we examined the viability and angiogenic properties of rat pulmonary artery endothelial cells upon exposure to either 21% or 1% oxygen, in presence of sildenafil (1 and 100 nM) and Epo (5 and 20 U/ml) alone or in combination (1 nM and 20 U/ml). Cell proliferation and viability were analyzed by Trypan blue staining, MTT assay, and Annexin V/propidium iodide stainings. In all assays, the ability of the combination treatment in improving cell viability was superior to that of either drug alone. The angiogenic properties were studied using a migration and a 3D collagen assay, and the results revealed increases in the migration potential of endothelial cells as well as the ability to form tube-like structures in response to sildenafil and the combination treatment. We therefore conclude that both drugs exert protective effects on endothelial cells on hypoxia and that sildenafil enhances the migratory and angiogenic properties, especially in hypoxic conditions. Furthermore, we present evidence of possible additive or synergistic effects of both drugs.

scholarly journals miRNAs in Extracellular Vesicles from iPS-Derived Cardiac Progenitor Cells Effectively Reduce Fibrosis and Promote Angiogenesis in Infarcted Heart

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Wanling Xuan ◽  
Lei Wang ◽  
Meifeng Xu ◽  
Neal L. Weintraub ◽  
Muhammad Ashraf
Keyword(s):  
Progenitor Cells ◽  
Extracellular Vesicles ◽  
Biologically Active ◽  
Attractive Potential ◽  
Cardiac Progenitor Cells ◽  
Cardiac Stem Cell ◽  
Regenerative Therapy ◽  
Beneficial Effects ◽  
Infarcted Heart ◽  
Postinfarction Remodeling

Cardiac stem cell therapy offers the potential to ameliorate postinfarction remodeling and development of heart failure but requires optimization of cell-based approaches. Cardiac progenitor cells (CPCs) induction by ISX-9, a small molecule possessing antioxidant, prosurvival, and regenerative properties, represents an attractive potential approach for cell-based cardiac regenerative therapy. Here, we report that extracellular vesicles (EV) secreted by ISX-9-induced CPCs (EV-CPCISX-9) faithfully recapitulate the beneficial effects of their parent CPCs with regard to postinfarction remodeling. These EV contain a distinct repertoire of biologically active miRNAs that promoted angiogenesis and proliferation of cardiomyocytes while ameliorating fibrosis in the infarcted heart. Amongst the highly enriched miRNAs, miR-373 was strongly antifibrotic, targeting 2 key fibrogenic genes, GDF-11 and ROCK-2. miR-373 mimic itself was highly efficacious in preventing scar formation in the infarcted myocardium. Together, these novel findings have important implications with regard to prevention of postinfarction remodeling.

scholarly journals Therapeutic Cell Protective Role of Histochrome under Oxidative Stress in Human Cardiac Progenitor Cells

Marine Drugs ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. 368 ◽  
Author(s):  
Ji Hye Park ◽  
Na-Kyung Lee ◽  
Hye Ji Lim ◽  
Sinthia Mazumder ◽  
Vinoth Kumar Rethineswaran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protective Effect ◽  
Progenitor Cells ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
B Cell Lymphoma ◽  
Cardiac Progenitor Cells ◽  
Protective Effects ◽  
Prolonged Incubation ◽  
Apoptotic Proteins

Cardiac progenitor cells (CPCs) are resident stem cells present in a small portion of ischemic hearts and function in repairing the damaged heart tissue. Intense oxidative stress impairs cell metabolism thereby decreasing cell viability. Protecting CPCs from undergoing cellular apoptosis during oxidative stress is crucial in optimizing CPC-based therapy. Histochrome (sodium salt of echinochrome A—a common sea urchin pigment) is an antioxidant drug that has been clinically used as a pharmacologic agent for ischemia/reperfusion injury in Russia. However, the mechanistic effect of histochrome on CPCs has never been reported. We investigated the protective effect of histochrome pretreatment on human CPCs (hCPCs) against hydrogen peroxide (H2O2)-induced oxidative stress. Annexin V/7-aminoactinomycin D (7-AAD) assay revealed that histochrome-treated CPCs showed significant protective effects against H2O2-induced cell death. The anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and Bcl-xL were significantly upregulated, whereas the pro-apoptotic proteins BCL2-associated X (Bax), H2O2-induced cleaved caspase-3, and the DNA damage marker, phosphorylated histone (γH2A.X) foci, were significantly downregulated upon histochrome treatment of hCPCs in vitro. Further, prolonged incubation with histochrome alleviated the replicative cellular senescence of hCPCs. In conclusion, we report the protective effect of histochrome against oxidative stress and present the use of a potent and bio-safe cell priming agent as a potential therapeutic strategy in patient-derived hCPCs to treat heart disease.

scholarly journals Differential Production of Cartilage ECM in 3D Agarose Constructs by Equine Articular Cartilage Progenitor Cells and Mesenchymal Stromal Cells

2020 ◽  
Vol 21 (19) ◽  
pp. 7071
Author(s):  
Stefanie Schmidt ◽  
Florencia Abinzano ◽  
Anneloes Mensinga ◽  
Jörg Teßmar ◽  
Jürgen Groll ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Type I Collagen ◽  
Type Ii Collagen ◽  
Cell Types ◽  
Type I ◽  
Cartilage Engineering ◽  
Hypoxic Conditions

Identification of articular cartilage progenitor cells (ACPCs) has opened up new opportunities for cartilage repair. These cells may be used as alternatives for or in combination with mesenchymal stromal cells (MSCs) in cartilage engineering. However, their potential needs to be further investigated, since only a few studies have compared ACPCs and MSCs when cultured in hydrogels. Therefore, in this study, we compared chondrogenic differentiation of equine ACPCs and MSCs in agarose constructs as monocultures and as zonally layered co-cultures under both normoxic and hypoxic conditions. ACPCs and MSCs exhibited distinctly differential production of the cartilaginous extracellular matrix (ECM). For ACPC constructs, markedly higher glycosaminoglycan (GAG) contents were determined by histological and quantitative biochemical evaluation, both in normoxia and hypoxia. Differential GAG production was also reflected in layered co-culture constructs. For both cell types, similar staining for type II collagen was detected. However, distinctly weaker staining for undesired type I collagen was observed in the ACPC constructs. For ACPCs, only very low alkaline phosphatase (ALP) activity, a marker of terminal differentiation, was determined, in stark contrast to what was found for MSCs. This study underscores the potential of ACPCs as a promising cell source for cartilage engineering.

1134-P: The Secretome of Visceral Adipose Cells Induces Apoptosis of Cardiac Progenitor Cells in Human Obesity: Protective Effects of the SGLT2 Inhibitor Dapagliflozin

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1134-P
Author(s):  
STEFANIA PORRO ◽  
SEBASTIO PERRINI ◽  
CRISTINA CACCIOPPOLI ◽  
ROSSELLA DORIA ◽  
VALENTINA ANNAMARIA GENCHI ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Sglt2 Inhibitor ◽  
Cardiac Progenitor Cells ◽  
Protective Effects ◽  
Human Obesity ◽  
Visceral Adipose ◽  
Adipose Cells

scholarly journals Combination of Cardiac Progenitor Cells From the Right Atrium and Left Ventricle Exhibits Synergistic Paracrine Effects In Vitro

2020 ◽  
Vol 29 ◽  
pp. 096368972097232
Author(s):  
Ryan McQuaig ◽  
Parul Dixit ◽  
Atsushi Yamauchi ◽  
Isabelle Van Hout ◽  
Jayanthi Bellae Papannarao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Growth Factor ◽  
Left Ventricle ◽  
Progenitor Cells ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Cardiac Repair ◽  
Cardiac Progenitor Cells ◽  
Paracrine Effects

Cardiovascular diseases, such as ischemic heart disease, remain the most common cause of death worldwide. Regenerative medicine with stem cell therapy is a promising tool for cardiac repair. Combination of different cell types has been shown to improve the therapeutic potential, which is thought to be due to synergistic or complimentary reparative effects. We investigated if the combination of cardiac progenitor cells (CPCs) of right atrial appendage (RAA) and left ventricle (LV) that are isolated from the same patient exert synergistic or complimentary paracrine effects for apoptotic cell death and angiogenesis in an in vitro model. Flow cytometry analysis showed that both RAA and LV CPCs expressed the mesenchymal cell markers CD90 and CD105, and were predominantly negative for the hematopoietic cell marker, CD34. Analysis of conditioned media (CM) collected from the CPCs cultured either alone or in combination in serum-deprived hypoxic conditions to simulate ischemia showed marked increase in the level of pro-survival hepatocyte growth factor and pro-angiogenic vascular endothelial growth factor-A in the combined RAA and LV CPC group. Next, to determine the therapeutic potential of CM, AC16 human ventricular cardiomyocytes and human umbilical vein endothelial cells (HUVECs) were treated with CM. Results showed a significant reduction in hypoxia-induced apoptosis of human cardiomyocytes treated with CM collected from combined RAA and LV CPC group. Similarly, matrigel assay showed a significantly increased tube length formed by HUVECs when treated with CM from combined RAA and LV CPC group. Our study provided evidence that the combination of RAA CPCs and LV CPCs may have superior therapeutic effects due to synergistic paracrine effects for cardiac repair. Therefore, in vivo studies are warranted to determine if a combination of different stem cell types have greater therapeutic potential than single-cell therapies.

Abstract 1845: Adult Cardiac Progenitor Cells Promote Angiogenesis and Cardioprotection through Their Secreted Soluble Vcam-1

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Katsuhisa Matsuura ◽  
Atsushi Honda ◽  
Toshio Nagai ◽  
Noritoshi Fukushima ◽  
Tatsuya Shimizu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Injury ◽  
Cell Sheet ◽  
Fold Increase ◽  
Neonatal Rat ◽  
Antibody Array ◽  
Cardiac Progenitor Cells ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Promising Source

Although cardiac progenitor cells have been thought to be the promising source of cell therapy, the precise mechanisms of their paracrine action have not been fully elucidated. Since we observed that the transplantation of clonal expanded Sca-1 positive cardiac progenitor cells (cSca-1 cells) derived from adult murine heart by using cell sheet technique improved cardiac function of infarcted heart compared to adipose tissue derived mesenchymal cells (ATMC), we explored the secreted factors highly expressed in cSca-1 cells and identified that soluble VCAM-1 (sVCAM-1) was much abundant in cSca-1 cells compared to ATMC by using cytokine antibody array. cSca-1 cells-derived conditioned medium (CM) significantly enhanced endothelial migration and matrigel tube formation and these effects were abolished by knock down of VCAM-1 (Fold increase: control, 1.0; CM, 2.97 ± 0.21; siVCAM-1, 1.98 ± 0.09; siControl, 2.76 ± 0.05, p<0.01), suggesting that cSca-1 cells promote angiogenesis via their secreted sVCAM-1. We next examined whether sVCAM-1 conferred direct protective effects on cardiomyocytes. We exposed cardiomyocytes to 0.2 mM H 2 O 2 in the absence or presence of sVCAM-1 or CM and examined cardiomyocyte viability by MTT assay. The exposure of cardiomyocytes to H 2 O 2 significantly induced the cell injury. Interestingly when pretreated with sVCAM-1 or CM, the cell damages of cardiomyocytes by H 2 O 2 were significantly reduced. However when pretreated with anti-VLA4 antibody, a principal coreceptor of sVCAM-1, CM mediated cell protected effect was completely inhibited (Fold increase: control, 1.0; anti-VLA4, 0.89 ± 0.33; sVCAM-1, 1.69 ± 0.27; CM, 2.08 ± 0.28; CM+anti-VLA4, 1.07 ± 0.07, p<0.01), suggesting that a crucial role of the VLA4 in inducing survival of cardiomyocytes by CM. sVCAM-1 and CM induced phosphorylation of FAK, Akt, Erk and p38 MAPK in neonatal rat cardiomyocytes. When pretreated with wortmannin, SB203580 and PD98059, the cardioprotective effects of sVCAM-1 and CM significantly inhibited, suggesting that sVCAM-1 might protect cardiomyocytes from oxidative stress via integrated upregulation of Akt, Erk and p38MAPK. These findings suggest cardiac progenitor cells promote angiogenesis and cardioprotection through their secreted sVCAM-1.

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