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.

scholarly journals Intracoronary Delivery of Porcine Cardiac Progenitor Cells Overexpressing IGF-1 and HGF in a Pig Model of Sub-Acute Myocardial Infarction

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2571
Author(s):  
Cristina Prat-Vidal ◽  
Verónica Crisóstomo ◽  
Isabel Moscoso ◽  
Claudia Báez-Díaz ◽  
Virginia Blanco-Blázquez ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Large Animal Model ◽  
Cardiac Progenitor Cells ◽  
Large Animal ◽  
Insulin Growth Factor ◽  
Decellularized Extracellular Matrix ◽  
Preclinical Animal Models

Human cardiac progenitor cells (hCPC) are considered a good candidate in cell therapy for ischemic heart disease, demonstrating capacity to improve functional recovery after myocardial infarction (MI), both in small and large preclinical animal models. However, improvements are required in terms of cell engraftment and efficacy. Based on previously published reports, insulin-growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) have demonstrated substantial cardioprotective, repair and regeneration activities, so they are good candidates to be evaluated in large animal model of MI. We have validated porcine cardiac progenitor cells (pCPC) and lentiviral vectors to overexpress IGF-1 (co-expressing eGFP) and HGF (co-expressing mCherry). pCPC were transduced and IGF1-eGFPpos and HGF-mCherrypos populations were purified by cell sorting and further expanded. Overexpression of IGF-1 has a limited impact on pCPC expression profile, whereas results indicated that pCPC-HGF-mCherry cultures could be counter selecting high expresser cells. In addition, pCPC-IGF1-eGFP showed a higher cardiogenic response, evaluated in co-cultures with decellularized extracellular matrix, compared with native pCPC or pCPC-HGF-mCherry. In vivo intracoronary co-administration of pCPC-IGF1-eGFP and pCPC-HFG-mCherry (1:1; 40 × 106/animal), one week after the induction of an MI model in swine, revealed no significant improvement in cardiac function.

Insulin-like growth factor-1 short-period therapy improves cardiomyopathy stimulating cardiac progenitor cells survival in obese mice

2020 ◽  
Vol 30 (1) ◽  
pp. 151-161 ◽  
Author(s):  
Daniela Andrade ◽  
Genilza Oliveira ◽  
Luciana Menezes ◽  
Ana Lúcia Nascimento ◽  
Simone Carvalho ◽  
...  
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Cardiac Progenitor Cells ◽  
Insulin Like Growth Factor ◽  
Obese Mice ◽  
Short Period

scholarly journals Growth Factor-Induced Mobilization of Cardiac Progenitor Cells Reduces the Risk of Arrhythmias, in a Rat Model of Chronic Myocardial Infarction

PLoS ONE ◽  
2011 ◽  
Vol 6 (3) ◽  
pp. e17750 ◽  
Author(s):  
Leonardo Bocchi ◽  
Monia Savi ◽  
Gallia Graiani ◽  
Stefano Rossi ◽  
Aldo Agnetti ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Rat Model ◽  
Cardiac Progenitor Cells ◽  
Chronic Myocardial Infarction

Abstract 3815: Pim-1 Gene Delivery to Cardiac Progenitor Cells Prevents Long Term Cardiac Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kimberlee Fischer ◽  
Weitao Wu ◽  
Christopher Cottage ◽  
Natalie Gude ◽  
Mark Sussman
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Left Ventricular ◽  
Functional Improvement ◽  
Cardiac Progenitor Cells ◽  
Intramyocardial Injection ◽  
Improved Performance ◽  
Enhance Stem Cell ◽  
Fractional Shortening

Cardiac stem cell therapy administered at the time of infarction effectively blunts cardiomyopathic damage a few weeks after treatment but long term efficacy of adoptive stem cell transfer remains largely unknown. A comparative analysis shows that long term (25 week) protection is only provided by Pim-1 modified progenitor cells whereas unmodified progenitor cells fail to provide prolonged benefits after six weeks post intramyocardial injection. After infarction mice were intramyocardially injected with saline, unmodified cardiac progenitor cells (CPC’s), or Pim-1 modified CPC’s. At a 12 week time point mice injected with Pim-1 modified CPC’s have increased EF and FS as compared to mice injected with unmodified cells (n=15 for each group). Invasive hemodynamic measurements (n=5 for each group) confirm that mice injected with Pim-1 modified CPC’s had improved performance by assessment of multiple functional criteria compared to unmodified cells. Longitudinal monitoring by echocardiography reveals that mice injected with Pim-1 modified CPC’s sustain fractional shortening and ejection fraction for up to 24 weeks whereas animals that receive unmodified cells begin to fail within 6 weeks after delivery and were not statistically different than saline injected controls after 12 weeks. In addition Pim-1 CPC injected mice had infarct sizes 52% smaller than control groups (p<.02). Both saline and unmodified CPC’s groups maintained similar infarct sizes (~60% of left ventricular free wall). Confocal microscopy reveals engraftment and persistence of injected Pim-1 CPC’s into the myocardium with differentiation into multiple cardiogenic lineages giving rise to myocytes, vasculature, and endothelium Successful long term functional improvement of the heart requires the engraftment of Pim-1 genetically modified cardiac progenitor cells. Unmodified cells offer an acute ameliorative response but ultimately fail in the ability to effectively repair and maintain the function of the heart. These results support use of genetic engineering to enhance stem cell-mediated myocardial regeneration.

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.

Abstract 1115: Impaired Angiogenic Potential of Cardiac Progenitor Cells in Mice with a Cardiomyocyte-Restricted Knock Out of STAT3

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Philipp Fischer ◽  
Ewa Missol-Kolka ◽  
Nils-Holger Zschemisch ◽  
Christian Templin ◽  
Helmut Drexler ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Adipocyte Differentiation ◽  
Prostaglandin E ◽  
Mouse Heart ◽  
Cardiac Progenitor Cells ◽  
Rt Pcr ◽  
Differentiation Potential ◽  
Intramyocardial Injection ◽  
Knock Out

Mice with a cardiomyocyte-restricted knock out of STAT3 (KO: alpha-MHC-Cre tg/+; STAT3 flox/flox ) show a continuous decrease of the cardiac capillary density and develop heart failure beyond the age of 9 months. We sought to determine the paracrine influence of cardiomyocyte STAT3 on the endothelial differentiation potential of cardiac progenitor cells (CPC) of the adult mouse heart. Sca-1 + CPC were isolated from male mice hearts by MACS separation. STAT3 was entirely deleted in cardiomyocytes of KO mice, while CPC from KO showed normal expression of STAT3 (confirmed by PCR and Western blot). No difference in the total number of CPC per heart was observed between wildtype (WT: STAT3 flox/flox ) and KO mice. FACS analysis revealed a reduced number of endothelial progenitor cells (as defined by coexpression of Sca-1, CD31 and CD38, −25%, P<0.05) among CPC from KO compared to CPC from WT. The differentiation potential of CPC from WT and KO was analyzed during in vitro culture on fibronectin-coated plates. After 4 weeks of culture RT-PCR for CD31 and immunohistochemistry (IHC) for endothelial cell (EC) marker tie2 and isolectin B4 was performed. CPC from WT showed markedly more efficient EC differentiation and tube formation compared to CPC from KO (p<0.01). In contrast, adipocyte differentiation was enhanced in CPC from KO (p<0.05, oil red staining and RT-PCR). Proliferation capacity of CPC from KO was reduced by 33% (p<0.01) as compared to CPC from WT. Microarray results of freshly isolated CPC were consistent with the differences in EC and adipocyte differentiation (i.e. prostaglandin E receptor 3 up 2.3-fold in CPC from WT, Lipocalin-2 up 2.7-fold in CPC from KO). We did not observe cardiomyocyte differentiation (IHC for alpha-sarcomeric actinin; RT-PCR for Nkx 2.5, alpha-MHC, or alpha-skeletal actin) of CPC from both genotypes, neither in vitro by addition of oxytocin, 5-AZA, DMSO, nor following intramyocardial injection of CPC in vivo. Conclusion: STAT3-dependent paracrine mediators released from cardiomyocytes are determinants of differentiation and vasculogenic properties of new EC derived from cardiac progenitor cells. The identification of these factors may offer new approaches to enforce the endogenous vasculogenic repair potential of the adult heart.

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.

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