Bone Marrow-Derived Stem Cells Attenuate Impaired Contractility and Enhance Capillary Density in a Rabbit Model of Doxorubicin-Induced Failing Hearts

Garbade, Jens; Dhein, Stefan; Lipinski, C; Aupperle, H.; Arsalan, Mani; Borger, Michael A.; Barten, M.J.; Lehmann, Sven; Walther, Thomas; Mohr, Friedrich–Wilhelm

doi:10.1111/j.1540-8191.2009.00844.x

Cited by 23 publications

(22 citation statements)

References 32 publications

(79 reference statements)

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“…Although its efficacy is widely accepted in the clinical arena in the aforementioned capacity, DOX has been shown to have dose-dependent deleterious effects on intrinsic cardiac architecture and function; these cardiotoxic consequences to include promotion of cardiac myocyte apoptosis, hypertrophy, enhanced susceptibility to MI, dilated cardiomyopathy, and impaired ejection fraction [5]–[8]. Limited studies have provided insight into the salutary impact propagated by transplanted stem cells in the DOX injured myocardium but, to date, no studies have been undertaken to elicit the effects of cellular therapy in the DOX-induced post-MI heart [16], [18], [24], [31]. In the present study, we have generated a DIC post infarction mouse model and evaluated the response of the injured myocardium to the transplanted ES and iPS cells as well as identified signaling molecules, including Notch-1, Hes1, PTEN, and Akt, which play a pivotal role in the cytoprotective mechanisms conferred by our transplanted stem cells.…”

Section: Discussionmentioning

confidence: 99%

“…Since cardiac myocytes have limited self-renewal, stem cells have acquired significant consideration as an alternative method to repair and regenerate cardiac cells [16]. Of note, human umbilical cord blood derived stem cells and bone marrow-derived stem cells have been shown to improve cardiac function and capillary density in DOX-induced cardiomyopathy (DIC) [16]–[18].…”

Section: Introductionmentioning

confidence: 99%

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Notch-1 Mediated Cardiac Protection following Embryonic and Induced Pluripotent Stem Cell Transplantation in Doxorubicin-Induced Heart Failure

Merino

Singla

2014

PLoS ONE

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Doxorubicin (DOX), an effective chemotherapeutic drug used in the treatment of various cancers, is limited in its clinical applications due to cardiotoxicity. Recent studies suggest that transplanted adult stem cells inhibit DOX-induced cardiotoxicity. However, the effects of transplanted embryonic stem (ES) and induced pluripotent stem (iPS) cells are completely unknown in DOX-induced left ventricular dysfunction following myocardial infarction (MI). In brief, C57BL/6 mice were divided into five groups: Sham, DOX-MI, DOX-MI+cell culture (CC) media, DOX-MI+ES cells, and DOX-MI+iPS cells. Mice were injected with cumulative dose of 12 mg/kg of DOX and 2 weeks later, MI was induced by coronary artery ligation. Following ligation, 5×104 ES or iPS cells were delivered into the peri-infarct region. At day 14 post-MI, echocardiography was performed, mice were sacrificed, and hearts were harvested for further analyses. Our data reveal apoptosis was significantly inhibited in ES and iPS cell transplanted hearts compared with respective controls (DOX-MI+ES: 0.48±0.06% and DOX-MI+iPS: 0.33±0.05% vs. DOX-MI: 1.04±0.07% and DOX-MI+CC: 0.96±0.21%; p<0.05). Furthermore, a significant increase in levels of Notch-1 (p<0.05), Hes1 (p<0.05), and pAkt (p<0.05) were observed whereas a decrease in the levels of PTEN (p<0.05), a negative regulator of Akt, was evident following stem cell transplantation. Moreover, hearts transplanted with stem cells demonstrated decreased vascular and interstitial fibrosis (p<0.05) as well as MMP-9 expression (p<0.01) compared with controls. Additionally, heart function was significantly improved (p<0.05) in both cell-transplanted groups. In conclusion, our data show that transplantation of ES and iPS cells blunt DOX-induced adverse cardiac remodeling, which is associated with improved cardiac function, and these effects are mediated by the Notch pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Notch-1 Mediated Cardiac Protection following Embryonic and Induced Pluripotent Stem Cell Transplantation in Doxorubicin-Induced Heart Failure

Merino

Singla

2014

PLoS ONE

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“…Human embryonic stem cells derived vascular cells and bone marrow derived multipotent progenitor cells following transplantation in the porcine infarcted heart improved cardiac function (36,37). Moreover, bone marrow derived stem cells or combined therapy with cardiomyocytes inhibits doxorubicin induced heart failure in rabbits (7,15,16). Unfortunately, adult stem cell transplanted clinical studies provided contentious reports on the improvement of cardiac function (9,21).…”

Section: Discussionmentioning

confidence: 99%

Embryonic Stem Cells Improve Cardiac Function in Doxorubicin-Induced Cardiomyopathy Mediated through Multiple Mechanisms

et al. 2012

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Doxorubicin (DOX) is an effective antineoplastic agent used for the treatment of a variety of cancers. Unfortunately, its use is limited as this drug induces cardiotoxicity and heart failure as a side effect. There is no report which describes whether transplanted embryonic stem (ES) cells or their conditioned medium (CM) in DOX induced cardiomyopathy (DIC) can repair and regenerate myocardium. Therefore, we transplanted ES cells or CM in DIC to examine apoptosis, fibrosis, cytoplasmic vacuolization and myofibrillar loss and their associated Akt and ERK pathway. Moreover, we also determined activation of endogenous c-kit+ve cardiac stem cells (CSCs), levels of HGF and IGF-1, growth factors required for c-kit cell activation, and their differentiation into cardiac myocytes, which also contributes in cardiac regeneration and improved heart function. We generated DIC in C57Bl/6 mice (cumulative dose of DOX 12mg/kg body weight, i.p), and animals were treated with ES cells, CM or cell culture medium in controls. Two weeks post-DIC, ES cells or CM transplanted hearts showed a significant (p<0.05) decrease in cardiac apoptotic nuclei and their regulation with Akt and ERK pathway. Cardiac fibrosis observed in the ES cell or CM groups was significantly less compared with DOX and cell culture medium groups (p<0.05). Next, cytoplasmic vacuolization and myofibrillar loss was reduced (p<0.05) following treatment with ES cells or CM. Moreover, our data also demonstrated increased levels of c-kit+ve CSCs in ES cells or CM hearts and differentiated cardiac myocytes from these CSCs, suggesting endogenous cardiac regeneration. Importantly, the levels of HFG and IGF-1 were significantly increased in ES cells or CM transplanted hearts. In conclusion, we reported that transplanted ES cells or CM in DIC hearts significantly decreases various adverse pathological mechanisms as well as enhances cardiac regeneration that effectively contributes to improved heart function.

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“…While the mechanisms underlying these observations is yet unknown, the possibility that MSCs may be mediating these effects via the release of paracrine factors is supported by the work conducted in this study and by others. In fact, the possibility that MSCs transdifferentiate was excluded by the same group in a recent report showingthat transplanted MSCs fail to express cardiac markers one month following transplantation [51]. …”

Section: Mesenchymal Stem Cellsmentioning

confidence: 99%

Paracrine mechanisms of stem cell reparative and regenerative actions in the heart

Mirotsou

Jayawardena

Schmeckpeper

et al. 2011

Journal of Molecular and Cellular Cardiology

426

317

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Stem cells play an important role in restoring cardiac function in the damaged heart. In order to mediate repair, stem cells need to replace injured tissue by differentiating into specialized cardiac cell lineages and/or manipulating the cell and molecular mechanisms governing repair. Despite early reports describing engraftment and successful regeneration of cardiac tissue in animal models of heart failure, these events appear to be infrequent and yield too few new cardiomyocytes to account for the degree of improved cardiac function observed. Instead, mounting evidence suggests that stem cell mediated repair takes place via the release of paracrine factors into the surrounding tissue that subsequently direct a number of restorative processes including myocardial protection, neovascularization, cardiac remodeling, and differentiation. The potential for diverse stem cell populations to moderate many of the same processes as well as key paracrine factors and molecular pathways involved in stem cell-mediated cardiac repair will be discussed in this review.

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Bone Marrow-Derived Stem Cells Attenuate Impaired Contractility and Enhance Capillary Density in a Rabbit Model of Doxorubicin-Induced Failing Hearts

Abstract: Despite local cell transplantation, autologous BMCs improve global contractility and enhance remote capillary density and collagen content in doxorubicin-induced cardiomyopathy. However, BMCs failed to transdifferentiate into new cardiomyocytes.

Cited by 23 publications

References 32 publications

Notch-1 Mediated Cardiac Protection following Embryonic and Induced Pluripotent Stem Cell Transplantation in Doxorubicin-Induced Heart Failure

Notch-1 Mediated Cardiac Protection following Embryonic and Induced Pluripotent Stem Cell Transplantation in Doxorubicin-Induced Heart Failure

Embryonic Stem Cells Improve Cardiac Function in Doxorubicin-Induced Cardiomyopathy Mediated through Multiple Mechanisms

Paracrine mechanisms of stem cell reparative and regenerative actions in the heart

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