Muscle differentiation during repair of myocardial necrosis in rats via gene transfer with MyoD.

Murry, Charles E.; Kay, Mark A.; Bartosek, Trudy; Hauschka, Stephen D.; Schwartz, Stephen M.

doi:10.1172/jci119030

Cited by 136 publications

(88 citation statements)

References 52 publications

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“…We posit that acute phase delivery of SDF-1α gene will mitigate the ongoing intrinsic molecular cascade involved in the cell death and fibrous scar formation in the ischemic myocardium. In this regard, viral vectors may show some efficiency in gene transfer to the necrotic myocardium which otherwise is resistant to direct gene transfer [27][28]. However, the strategy is not without untoward effects.…”

Section: Discussionmentioning

confidence: 99%

Ex vivo delivered stromal cell-derived factor-1α promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium

Elmadbouh

Haider

Jiang

et al. 2007

Journal of Molecular and Cellular Cardiology

167

110

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We aimed to optimize non-viral transfection of human stromal cell derived factor (SDF-1α) gene into skeletal myoblasts (SkM) and, transplant these cells to establish transient SDF-1α gradient to favor extra-cardiac stem cell translocation into infarcted heart. Optimized conditions for transfection of SDF-1α gene into syngenic SkM were achieved using FuGene™6/phSDF-1α (3:2v/w, 4h transfection) with 125μM ZnCl 2 (p<0.001). After characterization for transgene overexpression by immunostaining, ELISA, and PCR, the cells were transplanted in female rat model of myocardial infarction. Thirty-six rats were grouped (n=12/group) to receive 70μl DMEM without cells (group-1) or containing 1.5×10 6 non-transfected (group-2) or SDF-1α transfected SkM (group-3). On day-4 post-transplantation (in 4 animals/group), marked expression of SDF-1α/sry-gene (p=0.003), total Akt, phospho-Akt and Bcl2 was observed in group-3. The number of CD31 + , C-kit + and CD34 + cells was highest in group-3 hearts (p<0.01). Blood vessel density in group-3 was higher in both scar and peri-scar regions (p<0.001) as compared with other groups. Echocardiography showed improved indices of left ventricle contractile function and remodeling in group-3 (p<0.05) as compared with groups-1 and -2. We conclude that ex-vivo SDF-1α transgene delivery promotes stem and progenitor cell migration to the heart, activates cell survival signaling and enhances angiomyogenesis in the infarcted heart.

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Section: Discussionmentioning

confidence: 99%

Ex vivo delivered stromal cell-derived factor-1α promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium

Elmadbouh

Haider

Jiang

et al. 2007

Journal of Molecular and Cellular Cardiology

167

110

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“…Five-micron sections were stained with hematoxylin and eosin, or subjected to immunohistochemistry as previously described [8,49,99,101]. Hematoxylin was used as the nuclear counterstain in immunohistochemical studies.…”

Section: Histologymentioning

confidence: 99%

“…These studies showed that a panoply of cells injected into the myocardium both can change the nature of the scar and improve post-infarction cardiac function. Skeletal myoblasts [6][7][8], fetal or neonatal cardiomyocytes [9][10][11], fibroblasts [12], smooth muscle cells [13], hematopoietic stem cells [14,15], mesenchymal stem cells [16], endothelial cells [17], resident cardiac progenitor cells [18,19], and derivatives of human embryonic stem cells [20][21][22][23][24] have all been transplanted into animal hearts. While it is clear that functional benefit is conferred from numerous cell types, the mechanism of action is unclear.…”

Section: Introductionmentioning

confidence: 99%

Systems approaches to preventing transplanted cell death in cardiac repair

Robey

Saiget

Reinecke

et al. 2008

Journal of Molecular and Cellular Cardiology

365

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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“…Accordingly, QM(myc) represent an attractive model system to identify MyoD-specific target genes in myogenic cells as well as factors, acting upstream of the MyoD family, involved in the establishment and maintenance of the myogenic identity. (Murry et al, 1996). Multiplicity of infection ranged between 100 and 1000.…”

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confidence: 99%

Selective repression of myoD transcription by v-Myc prevents terminal differentiation of quail embryo myoblasts transformed by the MC29 strain of avian myelocytomatosis virus

et al. 2002

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We have investigated the mechanism by which expression of the v-myc oncogene interferes with the competence of primary quail myoblasts to undergo terminal differentiation. Previous studies have established that quail myoblasts transformed by myc oncogenes are severely impaired in the accumulation of mRNAs encoding the myogenic transcription factors Myf-5, MyoD and Myogenin. However, the mechanism responsible for such a repression remains largely unknown. Here we present evidence that v-Myc selectively interferes with quail myoD expression at the transcriptional level. Cisregulatory elements involved in the auto-activation of qmyoD are specifically targeted in this unique example of transrepression by v-Myc, without the apparent participation of Myc-specific E-boxes or InR sequences. Transiently expressed v-Myc efficiently interfered with MyoD-dependent transactivation of the qmyoD regulatory elements, while the myogenin promoter was unaffected. Finally, we show that forced expression of MyoD in v-myc-transformed quail myoblasts restored myogenin expression and promoted extensive terminal differentiation. These data suggest that transcriptional repression of qmyoD is a major and rate-limiting step in the molecular pathway by which v-Myc severely inhibits terminal differentiation in myogenic cells.

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Muscle differentiation during repair of myocardial necrosis in rats via gene transfer with MyoD.

Abstract: Myocardial infarcts heal by scar formation because there are no stem cells in myocardium, and because adult myocytes cannot divide and repopulate the wound. We sought to redirect the heart to form skeletal muscle instead of scar by transferring the myogenic determination gene, MyoD

Cited by 136 publications

References 52 publications

Ex vivo delivered stromal cell-derived factor-1α promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium

Ex vivo delivered stromal cell-derived factor-1α promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium

Systems approaches to preventing transplanted cell death in cardiac repair

Selective repression of myoD transcription by v-Myc prevents terminal differentiation of quail embryo myoblasts transformed by the MC29 strain of avian myelocytomatosis virus

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