scholarly journals After the Storm: An Objective Appraisal of the Efficacy of c-kit+ Cardiac Progenitor Cells in Preclinical Models of Heart Disease

2020 ◽  
Author(s):  
Roberto Bolli ◽  
Xian-Liang Tang ◽  
Yiru Guo ◽  
Qianhong Li
Keyword(s):  
Progenitor Cells ◽  
Ischemic Cardiomyopathy ◽  
Therapeutic Potential ◽  
Clinical Work ◽  
Good Faith ◽  
Cardiac Progenitor Cells ◽  
Review Of The Literature ◽  
Preclinical Models ◽  
Beneficial Effects ◽  
Retraction Notice

The falsification of data related to c-kit+ cardiac progenitor cells (CPCs) by a Harvard laboratory has been a veritable tragedy. Does this fraud mean that CPCs are not beneficial in models of ischemic cardiomyopathy? At least 50 studies from 26 laboratories independent of the Harvard group have reported beneficial effects of CPCs in mice, rats, pigs, and cats. The mechanism of action remains unclear. Our group has shown that CPCs do not engraft in the diseased heart, do not differentiate into new cardiac myocytes, do not regenerate dead myocardium, and thus work via paracrine mechanisms. A casualty of the misconduct at Harvard has been the SCIPIO trial, a collaboration between the Harvard group and the group in Louisville. The retraction of the SCIPIO paper was caused exclusively by issues with data generated at Harvard, not those generated in Louisville. In the retraction notice, the Lancet editors stated: “Although we do not have any reservations about the clinical work in Louisville that used the preparations from Anversa's laboratory in good faith, the lack of reliability regarding the laboratory work at Harvard means that we are now retracting this paper.” We must be careful not to dismiss all work on CPCs because of one laboratory’s misconduct. An unbiased review of the literature supports the therapeutic potential of CPCs for heart failure at the preclinical level.

scholarly journals Comparative Proteomic Analysis of Nuclear and Cytoplasmic Compartments in Human Cardiac Progenitor Cells. Functional Evaluation of IL1A and IMP3

2021 ◽  
Author(s):  
Guillermo Albericio ◽  
Susana Aguilar ◽  
Jose Luis Torán ◽  
Rosa Yañez ◽  
Juan Antonio López ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Therapeutic Potential ◽  
Global Analysis ◽  
Human Mesenchymal Stem Cells ◽  
Dual Function ◽  
Cardiac Progenitor Cells ◽  
Functional Evaluation ◽  
Label Free ◽  
Proteomic Approach ◽  
Migration Capacity

Abstract Clinical trials evaluating cardiac progenitor cells (CPC) demonstrated feasibility and safety, but no clear functional benefits. Therefore a deeper understanding of CPC biology is warranted to inform strategies capable to enhance their therapeutic potential. Here we have defined, using a label-free proteomic approach, the differential cytoplasmic and nuclear compartments of human CPC (hCPC). Global analysis of cytoplasmic repertoire in hCPC suggested an important hypoxia response capacity and active collagen metabolism. In addition, comparative analysis of the nuclear protein compartment identified a significant regulation of a small number of proteins in hCPC versus human mesenchymal stem cells (hMSC). Two proteins significantly upregulated in the hCPC nuclear compartment, IL1A and IMP3, showed also a parallel increase in mRNA expression in hCPC versus hMSC, and were studied further. IL1A, subjected to an important post-transcriptional regulation, was demonstrated to act as a dual-function cytokine with a plausible role in apoptosis regulation. The knockdown of the mRNA binding protein (IMP3) did not negatively impact hCPC viability, but reduced their proliferation and migration capacity. Analysis of a panel of putative candidate genes identified HMGA2 and PTPRF as IMP3 targets in hCPC. Therefore, they are potentially involved in hCPC proliferation/migration regulation.

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 Hypercapnia and Acidosis in Sepsis

2010 ◽  
Vol 112 (2) ◽  
pp. 462-472 ◽  
Author(s):  
Gerard Curley ◽  
Maya Contreras ◽  
Alistair D. Nichol ◽  
Brendan D. Higgins ◽  
John G. Laffey ◽  
...  
Keyword(s):  
Immune Response ◽  
Lung Injury ◽  
Therapeutic Potential ◽  
Adaptive Immune Response ◽  
Cytokine Signaling ◽  
Microbial Infection ◽  
Preclinical Models ◽  
Beneficial Effects ◽  
Lung Stretch ◽  
Substantial Morbidity

Acute respiratory distress syndrome is a devastating disease that causes substantial morbidity and mortality. Mechanical ventilation can worsen lung injury, whereas ventilatory strategies that reduce lung stretch, resulting in a "permissive" hypercapnic acidosis (HCA), improve outcome. HCA directly reduces nonsepsis-induced lung injury in preclinical models and, therefore, has therapeutic potential in these patients. These beneficial effects are mediated via inhibition of the host immune response, particularly cytokine signaling, phagocyte function, and the adaptive immune response. Of concern, these immunosuppressive effects of HCA may hinder the host response to microbial infection. Recent studies suggest that HCA is protective in the earlier phases of bacterial pneumonia-induced sepsis but may worsen injury in the setting of prolonged lung sepsis. In contrast, HCA is protective in preclinical models of early and prolonged systemic sepsis. Buffering of the HCA is not beneficial and may worsen pneumonia-induced injury.

scholarly journals Epicardial Transplantation of Cardiac Progenitor Cells Based Cells Sheets is More Promising Method for Stimulation of Myocardial Regeneration, Than Conventional Cell Injections

Kardiologiia ◽  
2019 ◽  
Vol 59 (5) ◽  
pp. 53-60 ◽  
Author(s):  
K. V. Dergilev ◽  
Z. I. Tsokolayeva ◽  
I. B. Beloglazova ◽  
E. I. Ratner ◽  
E. V. Parfyonova
Keyword(s):  
Progenitor Cells ◽  
Cardiac Remodeling ◽  
Progenitor Cell ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Cardiac Progenitor Cells ◽  
Cell Sheets ◽  
Intramyocardial Delivery ◽  
Conventional Cell ◽  
Stimulation Of

Today, transplantation of stem / progenitor cells is a promising approach for the treatment of heart diseases. The therapeutic potential of transplanted cells directly depends on the method of delivery to the myocardium, which determines their regenerative properties. It is important for the development of effective methods of cell therapy. In this paper, we performed a comparative study of efficacy of cardiac progenitor cell (CPC) transplantation by intramyocardial needle injections and by tissue engineering constructs (TEC) – “cell sheets” consisting of cells and their extracellular matrix. It has been shown, that transplantation of TEC in comparison with the intramyocardial delivery provides more extensive distribution and retains more proliferating cellular elements in the damaged myocardium, attenuates the negative cardiac remodeling of the left ventricle and promotes its vascularization.   

scholarly journals Comparative proteomic analysis of nuclear and cytoplasmic compartments in human cardiac progenitor cells

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Guillermo Albericio ◽  
Susana Aguilar ◽  
Jose Luis Torán ◽  
Rosa Yañez ◽  
Juan Antonio López ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Therapeutic Potential ◽  
Global Analysis ◽  
Human Mesenchymal Stem Cells ◽  
Dual Function ◽  
Cardiac Progenitor Cells ◽  
Label Free ◽  
Proteomic Approach ◽  
And Migration ◽  
Migration Capacity

AbstractClinical trials evaluating cardiac progenitor cells (CPC) demonstrated feasibility and safety, but no clear functional benefits. Therefore a deeper understanding of CPC biology is warranted to inform strategies capable to enhance their therapeutic potential. Here we have defined, using a label-free proteomic approach, the differential cytoplasmic and nuclear compartments of human CPC (hCPC). Global analysis of cytoplasmic repertoire in hCPC suggested an important hypoxia response capacity and active collagen metabolism. In addition, comparative analysis of the nuclear protein compartment identified a significant regulation of a small number of proteins in hCPC versus human mesenchymal stem cells (hMSC). Two proteins significantly upregulated in the hCPC nuclear compartment, IL1A and IMP3, showed also a parallel increase in mRNA expression in hCPC versus hMSC, and were studied further. IL1A, subjected to an important post-transcriptional regulation, was demonstrated to act as a dual-function cytokine with a plausible role in apoptosis regulation. The knockdown of the mRNA binding protein (IMP3) did not negatively impact hCPC viability, but reduced their proliferation and migration capacity. Analysis of a panel of putative candidate genes identified HMGA2 and PTPRF as IMP3 targets in hCPC. Therefore, they are potentially involved in hCPC proliferation/migration regulation.

Abstract 859: Hypoxia-activated CXCR4 Expression In Cardiac Progenitor Cells For Replenishing Stem Cell Pool In Acute Ischemic Myocardium

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yao Liang Tang ◽  
Leping Shen ◽  
Keping Qian ◽  
M. Ian Phillips
Keyword(s):  
Cardiac Function ◽  
Progenitor Cells ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Cxcr4 Expression ◽  
Ischemic Myocardium ◽  
Cardiac Progenitor Cells ◽  
Ventricular Performance ◽  
Cell Homing ◽  
Beneficial Effects

The resident cardiac progenitor cells (CPCs) have been identified in the adult myocardium, however, the CPC pool is rapidly depleted after acute myocardial infarction (AMI). The strategy to home ex vivo cultured CPCs to ischemic myocardium might be an important strategy to replenish resident CPC pool, and improve cardiac function. The CXC chemokine SDF-1α and its receptor CXCR4 have been identified as critical mediator for the ischemia-specific recruitment of progenitor cells, yet the level of CXCR4 expression in CPCs is quite low in normal conditions. Our previous studies showed that hypoxia can optimize CPCs via inducing functional CXCR4 expression in vitro, therefore, in this study, we want to investigate whether the transplantation of hypoxia treated CPCs (Hypo:CPCs) have the benefit of improving cardiac function resulted from increased cell homing in ischemic myocardium through mechanisms of hypoxia induced CXCR4 expression. To compare the homing capability between CPCs and Hypo:CPCs in response to endogenous SDF-1 signal in acute ischemic myocardium, we used retrovirus (pCL-MFG-β-gal) to label c-kit + Lin − CPCs with β-gal, and then injected labeled CPCs and Hypo:CPCs (1×10 6 ) intravenously via intra-jugular vein to mice 10 min after induction of MI in the C56BL/6 mice. We harvested the hearts 1d after cell transplantation to quantify the cell retention by chemiluminescent β-galactosidase assay. We observed that hypoxia treatment resulted in about 2.5 fold increase in β-gal cell recruitment in ischemic hearts (p<0.001, n=7– 8/group), however, AMD3100 can partially reduce Hypo:CPCs homing, therefore, the beneficial effects of Hypo:CPCs transplantation were mediated primarily through increasing cell homing via SDF-1:CXCR4 binding within the ischemic hearts. In addtion, the infusion of Hypo:CPCs also led to improved left ventricular performance, as assessed by LV development pressure by Millar catheter, by 23.67% compared with CPCs at 1 month after cell therapy (p<0.001, n=6/group). These results indicate that replenish CPC pool after AMI using ex vivo cultured CPC transplantation has significant beneficial effects on injured heart function dependent of hypoxia induced CXCR4 upregulation.

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