Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts

Yang, Yue; Qian, Hai; Huang, Jian; Geng, Yong–Jian; R, Gao; Dou, Ke Fei; Yang, Guo Sheng; Li, Jian Jun; Shen, Rui; He, Zuo Xiang; Lu, Minjie; Zhao, Shihua

doi:10.1093/eurheartj/ehn167

Cited by 107 publications

(91 citation statements)

References 31 publications

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“…Genetically modifying MSCs to overexpress chemokine receptors CXCR-4 or CCR-1 resulted in increased MSC engraftment to infarcted myocardium. 20,21 In an attempt to improve MSC therapeutic properties, MSCs were also genetically engineered for Akt overexpression to improve survival 39 and with the proangiogenic factor vascular endothelial growth factor 40 to promote angiogenesis. Although stable DNA-based genetic manipulations yielded encouraging data in animal in vivo models, its translation into the clinic is challenging because of long-term safety concerns, and often a transient expression is preferred over stable expression approaches.…”

Section: Discussionmentioning

confidence: 99%

mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation

Levy

Zhao

Mortensen

et al. 2013

Blood

171

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Section: Discussionmentioning

confidence: 99%

mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation

Levy

Zhao

Mortensen

et al. 2013

Blood

171

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“…Therefore, we cannot rule out that 1 cell type had survived preferentially. 51 However, because there was a considerable additional favorable effect of combined transplantation above single cell-type transplantation, it is suggested that both cell types were present in the graft of the CoT group, although the exact proportion could not be determined.…”

Section: Morphologymentioning

confidence: 99%

A New Direction for Cardiac Regeneration Therapy

Winter

Oorschot

Hogers

et al. 2009

Circ: Heart Failure

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Background-Adult human epicardium-derived cells (EPDCs), transplanted into the infarcted heart, are known to improve cardiac function, mainly through paracrine protection of the surrounding tissue. We hypothesized that this effect might be further improved if these supportive EPDCs were combined with cells that could possibly supply the ischemic heart with new cardiomyocytes. Therefore, we transplanted EPDCs together with cardiomyocyte progenitor cells that can generate mature cardiomyocytes in vitro. Methods and Results-EPDCs and cardiomyocyte progenitor cells were isolated from human adult atrial appendages, expanded in culture, and transplanted separately or together into the infarcted mouse myocardium (total cell number, 4ϫ10 5 ). Cardiac function was determined 6 weeks later (9.4T MRI). Coculturing increased proliferation rate and production of several growth factors, indicating a mutual effect. Cotransplantation resulted in further improvement of cardiac function compared with single cell-type recipients (PϽ0.05), which themselves demonstrated better function than vehicle-injected controls (PϽ0.05). However, in contrast to our hypothesis, no graft-derived cardiomyocytes were observed within the 6-week survival, supporting that not only EPDCs but also cardiomyocyte progenitor cells acted in a paracrine manner. Because injected cell number and degree of engraftment were similar between groups, the additional functional improvement in the cotransplantation group cannot be explained by an increased amount of secreted factors but rather by an altered type of secretion. Conclusion-EPDCs

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“…Previously published data showed that mesenchymal stem cells (MSCs) had been widely applied in regenerative medicine and exhibited beneficial effects on postinfarct hearts [1][2][3]. However, the therapeutic potential of MSCs is hindered by their low survival rate after transplantation in damaged myocardium.…”

Section: Introductionmentioning

confidence: 99%

“…They can not only attenuate the inflammation and oxidative stress to provide a better microenvironment for implanted MSCs after AMI, but also increase the anti-apoptotic capacity of MSCs itself under H/SD condition, of which, both make statins a convincing candidate to deal with the ''low survival'' problem of MSCs mentioned previously [3,[13][14][15]. Several signaling pathways have been implicated in this protective role of statins, including AMP-activated protein kinase (AMPK), Janus kinase/ signal transducers and activators of the transcription, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ ERK1/2) pathways [13,14,16].…”

Section: Introductionmentioning

confidence: 99%

Autophagy Activation: A Novel Mechanism of Atorvastatin to Protect Mesenchymal Stem Cells from Hypoxia and Serum Deprivation via AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

Zhang

Yang

Wang

et al. 2012

Stem Cells and Development

150

114

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Autophagy is a complex ''self-eating'' process and could be utilized for cell survival under stresses. Statins, which could reduce apoptosis in mesenchymal stem cells (MSCs) during both ischemia and hypoxia/serum deprivation (H/SD), have been proved to induce autophagy in some cell lines. We have previously shown that atorvastatin (ATV) could regulate AMP-activated protein kinase (AMPK), a positive modulator of autophagy, in MSCs. Thus, we hypothesized that autophagy activation through AMPK and its downstream molecule mammalian target of rapamycin (mTOR) may be a novel mechanism of ATV to protect MSCs from apoptosis during H/SD. Here, we demonstrated that H/SD induced autophagy in MSCs significantly as identified by increasing acidic vesicular organelle-positive cells, type II of light chain 3 (LC3-II) expression, and autophagosome formation. The levels of H/SD-induced apoptosis were increased by autophagy inhibitor 3-methyladenine (3-MA) while decreased by rapamycin, an autophagic inducer. ATV further enhanced the autophagic activity observed in MSCs exposed to H/SD. Treatment with 3-MA attenuated ATV-induced autophagy and abrogated the protective effects of ATV on MSC apoptosis, while rapamycin failed to cause additional effects on either autophagy or apoptosis compared with ATV alone. The phosphorylation of AMPK was upregulated whereas the phosphorylation of mTOR was downregulated in ATV-treated MSCs, which were both attenuated by AMPK inhibitor compound C. Further, treatment with compound C reduced the ATV-induced autophagy in MSCs under H/SD. These data suggest that autophagy plays a protective role in H/SD-induced apoptosis of MSCs, and ATV could effectively activate autophagy via AMPK/mTOR pathway to enhance MSC survival during H/SD.

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Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts

Cited by 107 publications

References 31 publications

mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation

mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation

A New Direction for Cardiac Regeneration Therapy

Autophagy Activation: A Novel Mechanism of Atorvastatin to Protect Mesenchymal Stem Cells from Hypoxia and Serum Deprivation via AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

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