Heat Shock Treatment Enhances Graft Cell Survival in Skeletal Myoblast Transplantation to the Heart

Suzuki, Ken; Smoleński, Ryszard T.; Jayakumar, Jay; Murtuza, Bari; Brand, Nigel J.; Yacoub, Magdi H.

doi:10.1161/01.cir.102.suppl_3.iii-216

Cited by 102 publications

(79 citation statements)

References 23 publications

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“…The suggestion that stem cells have an increased resistance to oxidative stress compared with their more differentiated progeny has been described previously (Dernbach et al, 2004;He et al, 2004). Other studies focused on the importance of stress in the transplantation process by genetically engineering the transplanted cell population to resist the effects of inflammation and stress, most notably with heat-shock proteins (Suzuki et al, 2000;Zhang et al, 2001). In this study we extend these findings by showing that the MDSCs' superior antioxidant capacity not only improves its regenerative capacity in skeletal and cardiac muscle but enhances the host tissue's ability to mitigate adverse remodeling in the case of infracted myocardium.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the respiratory burst of inflammatory cells such local ischemia can further induce ROS production via xanthine oxidase conversion from xanthine dehydrogenase. (Chanock et al, 1994;Nishino, 1994;Gute et al, 1998;Makazan et al, 2007).Multiple groups have shown that stem cells appear to have an increased antioxidant capacity (Dernbach et al, 2004;He et al, 2004), whereas others have demonstrated the deleterious role of inflammation and oxidative stress in cell transplantation (Qu et al, 1998;Suzuki et al, 2000). Our group has shown that MDSCs have lower rates of stressinduced cell death, and we have speculated that the MDSCs' increased regenerative capacity may relate to an increased resistance to oxidative and inflammatory stress Deasy et al, 2007).…”

mentioning

confidence: 81%

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Antioxidant Levels Represent a Major Determinant in the Regenerative Capacity of Muscle Stem Cells

Urish

Vella

Okada³

et al. 2009

MBoC

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Stem cells are classically defined by their multipotent, long-term proliferation, and self-renewal capabilities. Here, we show that increased antioxidant capacity represents an additional functional characteristic of muscle-derived stem cells (MDSCs). Seeking to understand the superior regenerative capacity of MDSCs compared with myoblasts in cardiac and skeletal muscle transplantation, our group hypothesized that survival of the oxidative and inflammatory stress inherent to transplantation may play an important role. Evidence of increased enzymatic and nonenzymatic antioxidant capacity of MDSCs were observed in terms of higher levels of superoxide dismutase and glutathione, which appears to confer a differentiation and survival advantage. Further when glutathione levels of the MDSCs are lowered to that of myoblasts, the transplantation advantage of MDSCs over myoblasts is lost when transplanted into both skeletal and cardiac muscles. These findings elucidate an important cause for the superior regenerative capacity of MDSCs, and provide functional evidence for the emerging role of antioxidant capacity as a critical property for MDSC survival post-transplantation. INTRODUCTIONMyogenic cell transplantation has been proposed as a promising therapeutic approach in the treatment of skeletal and cardiac muscle injury. Early studies of myoblast transplantation into dystrophic skeletal muscle yielded limited regeneration of dystrophin-expressing muscle fibers (Beauchamp et al., 1994;Gussoni et al., 1997;Qu-Petersen et al., 2002). Similarly, given the limited regenerative ability of cardiac muscle, cell transplantation has been proposed as an alternative to heart transplantation (Assmus et al., 2006;Lunde et al., 2006;Schachinger et al., 2006).A major obstacle in both cardiac and skeletal myogenic therapies is the poor rate of engraftment of myogenic cells after transplantation (Taylor et al., 1998;Oshima et al., 2005). In skeletal muscle, numerous groups have observed a rapid inflammatory response that appears to contribute to rapid cell loss and limit therapeutic success (Beauchamp et al., 1994;Gussoni et al., 1997;Beauchamp et al., 1999). Multiple groups have postulated that the small number of injected cells that survive transplantation in both cardiac and skeletal muscle may represent a special subpopulation of stem-like cells (Qu et al., 1998;Beauchamp et al., 1999;Qu-Petersen et al., 2002).For these reasons, our group attempted to isolate this putative subpopulation of cells using a modified preplate technique. This procedure was initially developed to purify myoblasts from nonmyogenic cells, including fibroblasts, of whole tissue preparations based on the differential adhesion characteristics of the cells to a collagen coated flask (Rando and Blau, 1994). Our group modified this technique to isolate various populations of myogenic cells, including a population of early adhering preplate (EP) cells and a late adhering preplate (LP) cell population from which a subpopulation of long-term proliferating (LTP) cells,...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 81%

Antioxidant Levels Represent a Major Determinant in the Regenerative Capacity of Muscle Stem Cells

Urish

Vella

Okada³

et al. 2009

MBoC

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“…Because CEPO had no confounding effect on hematocrit, we studied it further for combinatorial treatments. As reviewed above, heat shock has been reported to increase survival of skeletal myoblasts [54,93], neonatal rat cardiomyocytes [40] and hESC-derived cardiomyocytes [105] following transplantation into the injured heart. In accordance with these data, heat shock resulted in a 5.1-fold increase in myoblast graft size determined by β-gal luminometry at 3 days (Figure 4).…”

Section: Effects Of Epo Cepo and Heat Shock On Skeletal Muscle Graftmentioning

confidence: 96%

“…Clonal populations of C2C12 cells stably transduced with a retrovirus encoding nuclear-localized β-gal [91] were expanded for use in this assay. β-gal labeled C2C12 cells have been previously delivered to the heart and measured by histology [92,93], establishing β-gal as a high-fidelity marker for grafted cells.…”

Section: β-Galactosidase As a Marker For Grafted Skeletal Myoblastsmentioning

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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“…Certaines pistes sont à l'étude, telles que la modification génétique par introduction de gènes anti-apoptotiques. L'activation non spécifique des protéines de choc thermique, par une simple élévation transitoire de la tempéra-ture des incubateurs, serait quant à elle d'une applicabilité clinique plus immédiate [125]. Enfin, l'intégration in vitro des cellules à des matrices artificielles pourrait permettre de résoudre une partie des problèmes liés à leur survie et à leur distribution [8,126].…”

Section: Caractérisation Des Cellulesunclassified

Thérapie cellulaire de l’insuffisance cardiaque

Vilquin

Marolleau

2004

Med Sci (Paris)

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L'insuffisance cardiaque devient un problème majeur de santé publique et, avec l'accroissement de la longé-vité, représentera la première cause de morbi-mortalité au XXI e siècle [1,2]. De plus, la prise en charge pharmacologique et hospitalière de l'insuffisance cardiaque représente 1 % à 2 % des dépenses de santé publique dans les pays occidentaux [1]. Les développements pharmacologiques en ont prodigieusement amé-lioré le pronostic. Cependant, s'ils améliorent la survie, la mortalité reste élevée et peut atteindre 60 % à un an pour des sujets au stade IV de la classification de la New York Heart Association (NYHA). Par ailleurs, la pathologie peut devenir réfractaire à ces approches théra-peutiques. Dans de nombreux cas, l'insuffisance cardiaque se développe à la suite d'un accident ischémique (infarctus du myocarde). L'anoxie, puis le développement de foyers inflammatoires importants, entraînent la mort ou la destruction des cardiomyocytes adultes responsables de la contraction myocardique. À la différence des urodèles [3], les mammifères ne semblent pas capables de régénérer les cardiomyocytes adultes, du moins de façon significative (voir ci-dessous), et la perte est donc massive et irréversible. La zone cardiaque ainsi ischémiée est remplacée par un tissu cicatriciel fibreux, akinétique. Cette perte de fonction se répercute sur la structure globale du myocarde qui subit un remodelage progressif, primitivement bénéfique, mais progressivement délétère puisqu'il mène à une modification de la géométrie cardiaque (dilatation) et à une désorganisation des interactions entre les cardiomyocytes survivants (‹). L'insuffisance cardiaque peut également se développer en l'absence d'accident ischémique aigü : certaines formes sont d'origine génétique (monogénique), lorsque des mutations altèrent la fonction de protéines impliquées dans > L'insuffisance cardiaque est un problème majeur de santé publique dans les pays industrialisés, et sa thé-rapeutique incomplètement efficace. C'est pourquoi la thérapie cellulaire a été développée comme nouvelle stratégie visant à améliorer la structure et la fonction du myocarde défaillant. Cet article décrit les différents types cellulaires envisagés dans cette perspective, ainsi que les premiers essais cliniques entrepris. La plupart des études ont été menées dans le cadre de l'insuffisance cardiaque post-ischémique. La transplantation de cardiomyocytes foetaux ou néonataux améliore chez l'animal la performance cardiaque, mais des problèmes immunologiques, logistiques et éthiques bloquent les perspectives cliniques d'une telle utilisation chez l'homme. En revanche, il semble que des cardiomyocytes adultes, autologues, pourraient être préparés à partir de cellules souches pré-sentes dans différents tissus (moelle osseuse, vaisseaux, coeur adulte, tissu adipeux). Par ailleurs, des précurseurs vasculaires issus de la moelle osseuse ou du sang circulant pourraient promouvoir la néo-angiogenèse au sein du myocarde infarci, stimulant ainsi un pool de cardiomyocytes hibernants. L'utilisat...

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Heat Shock Treatment Enhances Graft Cell Survival in Skeletal Myoblast Transplantation to the Heart

Cited by 102 publications

References 23 publications

Antioxidant Levels Represent a Major Determinant in the Regenerative Capacity of Muscle Stem Cells

Antioxidant Levels Represent a Major Determinant in the Regenerative Capacity of Muscle Stem Cells

Systems approaches to preventing transplanted cell death in cardiac repair

Thérapie cellulaire de l’insuffisance cardiaque

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