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

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.

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1763-P: The Secretome from Visceral Adipose Stem Cells of Obese Subjects Induces Apoptosis and Insulin Resistance in Cardiac Progenitor Cells

Diabetes ◽

10.2337/db19-1763-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 1763-P

Author(s):

STEFANIA PORRO ◽

SEBASTIO PERRINI ◽

CRISTINA CACCIOPPOLI ◽

ROSSELLA DORIA ◽

VALENTINA ANNAMARIA GENCHI ◽

...

Keyword(s):

Insulin Resistance ◽

Stem Cells ◽

Progenitor Cells ◽

Adipose Stem Cells ◽

Cardiac Progenitor Cells ◽

Obese Subjects ◽

Visceral Adipose

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

Circulation Research ◽

10.1161/res.113.suppl_1.a018 ◽

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.

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

Circulation ◽

10.1161/circ.118.suppl_18.s_396-c ◽

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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Cardiac progenitor cells in terminally failing hearts: Immunohistological observations in human myocardium

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-2007-967414 ◽

2007 ◽

Vol 55 (S 1) ◽

Author(s):

M Arnold ◽

V Kufer ◽

A Schütz ◽

B Reiter ◽

M Fittkau ◽

...

Keyword(s):

Progenitor Cells ◽

Human Myocardium ◽

Cardiac Progenitor Cells

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Breakthrough Regenerative Cardiopoietic Stem Cells and Related Technologies in the Field of Cardiovascular Medicine – From Bench to Bedside

Interventional Cardiology Review ◽

10.15420/icr.2012.7.1.14 ◽

2012 ◽

Vol 7 (1) ◽

pp. 14

Author(s):

Christian Homsy ◽

Keyword(s):

Stem Cells ◽

Cell Therapy ◽

Progenitor Cells ◽

Cardiac Disease ◽

Cardiac Tissue ◽

Cardiac Repair ◽

Cardiac Diseases ◽

Cardiac Progenitor Cells ◽

Biotechnology Company ◽

Cardiovascular Medicine

The scale of cardiac diseases, and in particular heart failure and acute myocardial infarction, emphasises the need for radically new approaches, such as cell therapy, to address the underlying cause of the disease, the loss of functional myocardium. Stem cell-based therapies, whether through transplanted cells or directing innate repair, may provide regenerative approaches to cardiac diseases by halting, or even reversing, the events responsible for progression of organ failure. Cardio3 BioSciences, a leading Belgian biotechnology company focused on the discovery and development of regenerative and protective therapies for the treatment of cardiac disease, was founded in this context in 2004. The company is developing a highly innovative cell therapy approach based on a platform designed to reprogramme the patient’s own stem cells into cardiac progenitor cells. The underlying rationale behind this approach is that, in order to reconstruct cardiac tissue, stem cells need to be specific to cardiac tissue. The key is therefore to provide cardiac-specific progenitor cells to the failing heart to induce cardiac repair.

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Diabetes induces dysregulation of microRNAs associated with survival, proliferation and self-renewal in cardiac progenitor cells

Diabetologia ◽

10.1007/s00125-021-05405-7 ◽

2021 ◽

Author(s):

Nima Purvis ◽

Sweta Kumari ◽

Dhananjie Chandrasekera ◽

Jayanthi Bellae Papannarao ◽

Sophie Gandhi ◽

...

Keyword(s):

Progenitor Cells ◽

Cardiac Progenitor Cells ◽

Self Renewal

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Novel Identified Circular Transcript of RCAN2, circ-RCAN2, Shows Deviated Expression Pattern in Pig Reperfused Infarcted Myocardium and Hypoxic Porcine Cardiac Progenitor Cells In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms22031390 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1390

Author(s):

Julia Mester-Tonczar ◽

Patrick Einzinger ◽

Johannes Winkler ◽

Nina Kastner ◽

Andreas Spannbauer ◽

...

Keyword(s):

Myocardial Infarction ◽

Progenitor Cells ◽

Regulatory Networks ◽

Circular Rnas ◽

Cardiac Progenitor Cells ◽

Tissue Samples ◽

Healthy Myocardium ◽

Acute Mi

Circular RNAs (circRNAs) are crucial in gene regulatory networks and disease development, yet circRNA expression in myocardial infarction (MI) is poorly understood. Here, we harvested myocardium samples from domestic pigs 3 days after closed-chest reperfused MI or sham surgery. Cardiac circRNAs were identified by RNA-sequencing of rRNA-depleted RNA from infarcted and healthy myocardium tissue samples. Bioinformatics analysis was performed using the CIRIfull and KNIFE algorithms, and circRNAs identified with both algorithms were subjected to differential expression (DE) analysis and validation by qPCR. Circ-RCAN2 and circ-C12orf29 expressions were significantly downregulated in infarcted tissue compared to healthy pig heart. Sanger sequencing was performed to identify the backsplice junctions of circular transcripts. Finally, we compared the expressions of circ-C12orf29 and circ-RCAN2 between porcine cardiac progenitor cells (pCPCs) that were incubated in a hypoxia chamber for different time periods versus normoxic pCPCs. Circ-C12orf29 did not show significant DE in vitro, whereas circ-RCAN2 exhibited significant ischemia-time-dependent upregulation in hypoxic pCPCs. Overall, our results revealed novel cardiac circRNAs with DE patterns in pCPCs, and in infarcted and healthy myocardium. Circ-RCAN2 exhibited differential regulation by myocardial infarction in vivo and by hypoxia in vitro. These results will improve our understanding of circRNA regulation during acute MI.

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