Enhancement of the functional benefits of skeletal myoblast transplantation by means of coadministration of hypoxia-inducible factor 1α

Azarnoush, Kasra; Maurel, A.; Sebbah, Laurent; Carrion, Claire; Bissery, Alvine; Mandet, Chantal; Pouly, Julia; Bruneval, Patrick; Hagège, Albert; Menasché, Philippe

doi:10.1016/j.jtcvs.2004.11.044

Cited by 72 publications

(46 citation statements)

References 34 publications

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“…In any case, vascularization is clearly required for long term graft survival, and several studies have found over-expression of vascular endothelial growth factor (VEGF) enhances grafted cell survival [74][75][76]. Interestingly, adenoviral over-expression of hypoxia inducible factor-1α (HIF-1α) [77] with grafted skeletal myoblasts increased graft cell number, blood vessel formation and cardiac function. Although direct pro-survival effects of HIF-1α expression in myoblasts may have occurred, another potential benefit is increased vascularization by angiogenic molecules induced by HIF-1α, such as VEGF.…”

Section: Strategies To Increase Cell Survivalmentioning

confidence: 99%

Systems approaches to preventing transplanted cell death in cardiac repair

Robey

Saiget

Reinecke

et al. 2008

Journal of Molecular and Cellular Cardiology

367

294

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Stem cell transplantation may repair the injured heart, but tissue regeneration is limited by death of transplanted cells. Most cell death occurs in the first few days post-transplantation, likely from a combination of ischemia, anoikis and inflammation. Interventions known to enhance transplanted cell survival include heat shock, over-expressing anti-apoptotic proteins, free radical scavengers, anti-inflammatory therapy and co-delivery of extracellular matrix molecules. Combinatorial use of such interventions markedly enhances graft cell survival, but death still remains a significant problem. We review these challenges to cardiac cell transplantation and present an approach to systematically address them.Most anti-death studies use histology to assess engraftment, which is time-and labor-intensive. To increase throughput, we developed two biochemical approaches to follow graft viability in the mouse heart. The first relies on LacZ enyzmatic activity to track genetically modified cells, and the second quantifies human genomic DNA content using repetitive Alu sequences. Both show linear relationships between input cell number and biochemical signal, but require correction for the time lag between cell death and loss of signal. Once optimized, they permit detection of as few as 1 graft cell in 40,000 host cells. Pro-survival effects measured biochemically at three days predict long-term histological engraftment benefits. These methods permitted identification of carbamylated erythropoietin (CEPO) as a pro-survival factor for human embryonic stem cell-derived cardiomyocyte grafts. CEPO's effects were additive to heat shock, implying independent survival pathways. This system should permit combinatorial approaches to enhance graft viability in a fraction of the time required for conventional histology.

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Section: Strategies To Increase Cell Survivalmentioning

confidence: 99%

Systems approaches to preventing transplanted cell death in cardiac repair

Robey

Saiget

Reinecke

et al. 2008

Journal of Molecular and Cellular Cardiology

367

294

View full text Add to dashboard Cite

show abstract

“…This is consistent with a high rate of cell death, which is incompletely compensated for by in vivo proliferation within the scar. 15 Cell manipulations to increase graft proliferation, survival, and electrical coupling with the host tissue 16 look to further enhance safety and efficacy of myoblast engraftment. 17 Nevertheless, the majority of the patients still exhibited at least 1 improved segment at end of FU.…”

Section: Hagège Et Al Myoblast Transplantation In Ischemic Heart Failmentioning

confidence: 99%

Skeletal Myoblast Transplantation in Ischemic Heart Failure

et al. 2006

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Background-Skeletal myoblast (SM) transplantation (Tx) in a post-myocardial infarction (MI) scar experimentally improves left ventricular (LV) ejection fraction (EF). Short-term follow-up (FU) studies have suggested that a similar benefit could clinically occur despite an increased risk of LV arrhythmias. Methods and Results-We report the long-term FU of the first worldwide cohort of grafted patients (n ϭ9, 61.8Ϯ11.6 years, previous MI, EF Յ35%) operated on (autologous SM Tx and bypass surgery) in 2000 to 2001 and evaluated before Tx, at 1 month (M1) and at a median FU of 52 (18 to 58) months after Tx (37 patient-years). NYHA class improved from 2.5Ϯ0.5 to 1.8Ϯ0.4 at M1 (Pϭ0.004 versus baseline) and 1.7Ϯ0.5 at FU (Pϭnot significant versus M1; Pϭ0.0007 versus baseline). EF increased from 24.3Ϯ4% to 31Ϯ4.1% at M1 (ϩ28%, Pϭ0.001 versus baseline) and remained stable thereafter (28.7Ϯ8.1%, ϩ18% versus baseline). There were 5 hospitalizations for heart failure in 3 patients at 28.6Ϯ9.9 months, allowing implant in 2 patients with a resynchronization pacemaker. An automatic cardiac defibrillator (ACD) was implanted in 5 patients for nonsustained (n ϭ1) or sustained (n ϭ4) ventricular tachycardia at 12.2Ϯ18.6 (1 to 45) months. Despite a beta-blocker/amiodarone combination therapy, there were 14 appropriate shocks for 3 arrhythmic storms in 3 patients at 6, 7, and 18 months after ACD implantation. Conclusions-In this cohort of severe heart failure patients both clinical status and EF stably improve over time with a strikingly low incidence of hospitalizations for heart failure (0.13/patient-years) and the arrhythmic risk can be controlled by medical therapy and/or on-request ACD implantation.

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“…23 More than 90% of autologous skeletal myoblasts underwent apoptosis or necrosis at 24 h after transplantation. 24 Therefore, a strategy to improve the survival and differentiation of transplanted cells in the infarction site is critical for improving the efficiency of stem cell therapy.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Csx/Nkx2.5 and GATA-4 Enhances the Efficacy of Mesenchymal Stem Cell Transplantation After Myocardial Infarction

Gao

Tan

Wang

2011

Circ J

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Background:The high death rate of the transplanted stem cells in the infarcted heart and low efficiency of differentiation toward cardiomyocytes show that mesenchymal stem cell (MSC) transplantation after myocardial infarction (MI) is not effective. Csx/Nkx2.5 and GATA-4 are considered to be key regulators of cardiogenesis. The aim of the present study was to investigate the effect of transplanting MSC overexpressing Csx/Nkx2.5 and GATA-4 (MSCs-CG) after MI. Methods and Results:According to acridine orange/ethidium bromide staining, MSCs-CG were more resistant to anoxia as compared with MSCs in vitro. In a mouse MI model, ejection fraction and fractional shortening were higher in the MSC-CG group than in the MSC or phosphate-buffered saline group. Wall thickness of the infarct area was increased and collagen deposition was clearly reduced in the MSC-CG group as compared with the other groups. There were more surviving MSCs in the MSC-CG group than in the MSC group. Most of the Y chromosome-positive cells expressed cardiac troponin T and connexin43 (Cx-43). Cx-43 was localized between Y chromosome-positive cells and recipient cardiomyocytes. Microvessel density in the peri-infarct regions and infarct regions increased significantly in the MSC-CG group.Conclusions: Transplantation of MSCs overexpressing Csx/Nkx2.5 and GATA-4 represents a new treatment strategy with the potential to improve cardiac function after MI. (Circ J 2011; 75: 2683 - 2691

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Enhancement of the functional benefits of skeletal myoblast transplantation by means of coadministration of hypoxia-inducible factor 1α

Abstract: Induction of angiogenesis is an effective means of potentiating the functional benefits of myoblast transplantation, and hypoxia-inducible factor 1alpha can successfully achieve this goal.

Cited by 72 publications

References 34 publications

Systems approaches to preventing transplanted cell death in cardiac repair

Systems approaches to preventing transplanted cell death in cardiac repair

Skeletal Myoblast Transplantation in Ischemic Heart Failure

Overexpression of Csx/Nkx2.5 and GATA-4 Enhances the Efficacy of Mesenchymal Stem Cell Transplantation After Myocardial Infarction

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