The future of regenerating the myocardium

Kuraitis, Drew; Suuronen, Erik J.; Sellke, Frank W.; Ruel, Marc

doi:10.1097/hco.0b013e32833f0318

Cited by 17 publications

(12 citation statements)

References 68 publications

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“…However, despite the emerging concept that satellite and endothelial cells co-operatively interact during angio-myogenesis [37], [38] and that VEGF plays an essential role in this bidirectional interaction [39], the involvement of this growth factor on muscle repair/regeneration has been poorly characterized. Of interest, recent observations show that VEGF is up-regulated in hypertrophic and hypoxic myofibres [40], [41], providing the basis for considering VEGF as a multifaceted factor for muscle growth and survival.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow Mesenchymal Stromal Cells Stimulate Skeletal Myoblast Proliferation through the Paracrine Release of VEGF

et al. 2012

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Mesenchymal stromal cells (MSCs) are the leading cell candidates in the field of regenerative medicine. These cells have also been successfully used to improve skeletal muscle repair/regeneration; however, the mechanisms responsible for their beneficial effects remain to be clarified. On this basis, in the present study, we evaluated in a co-culture system, the ability of bone-marrow MSCs to influence C2C12 myoblast behavior and analyzed the cross-talk between the two cell types at the cellular and molecular level. We found that myoblast proliferation was greatly enhanced in the co-culture as judged by time lapse videomicroscopy, cyclin A expression and EdU incorporation. Moreover, myoblasts immunomagnetically separated from MSCs after co-culture expressed higher mRNA and protein levels of Notch-1, a key determinant of myoblast activation and proliferation, as compared with the single culture. Notch-1 intracellular domain and nuclear localization of Hes-1, a Notch-1 target gene, were also increased in the co-culture. Interestingly, the myoblastic response was mainly dependent on the paracrine release of vascular endothelial growth factor (VEGF) by MSCs. Indeed, the addition of MSC-derived conditioned medium (CM) to C2C12 cells yielded similar results as those observed in the co-culture and increased the phosphorylation and expression levels of VEGFR. The treatment with the selective pharmacological VEGFR inhibitor, KRN633, resulted in a marked attenuation of the receptor activation and concomitantly inhibited the effects of MSC-CM on C2C12 cell growth and Notch-1 signaling. In conclusion, this study provides novel evidence for a role of MSCs in stimulating myoblast cell proliferation and suggests that the functional interaction between the two cell types may be exploited for the development of new and more efficient cell-based skeletal muscle repair strategies.

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Section: Discussionmentioning

confidence: 99%

Bone Marrow Mesenchymal Stromal Cells Stimulate Skeletal Myoblast Proliferation through the Paracrine Release of VEGF

et al. 2012

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“…We used a young, otherwise healthy porcine model of chronic ischemia. Most regenerative therapies are positive in these “normal” models, and nearly all preclinical studies utilizing diseased models such as a high‐fat–fed models are negative, as are nearly all clinical trials 25, 26, 27, 28. Finally, we used male pigs in our current research to decrease variability; in the future we will use female pigs as well.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicle Injection Improves Myocardial Function and Increases Angiogenesis in a Swine Model of Chronic Ischemia

Potz

Scrimgeour

Pavlov

et al. 2018

JAHA

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BackgroundMesenchymal stem cell–derived extracellular vesicles (EVs) are believed to be cardioprotective in myocardial infarct. The objective of this study was to examine the effects of human mesenchymal cell–derived EV injection on cardiac function, myocardial blood flow, and vessel density in the setting of chronic myocardial ischemia.Methods and ResultsTwenty‐three Yorkshire swine underwent placement of an ameroid constrictor on their left circumflex artery. Two weeks later, the animals were split into 2 groups: the control group (CON; n=7) and the EV myocardial injection group (MVM; n=10). The MVM group underwent myocardial injection of 50 μg of EVs in 2 mL 0.9% saline into the ischemic myocardium. Five weeks later, the pigs underwent a harvest procedure, and the left ventricular myocardium was analyzed. Absolute blood flow and the ischemic/nonischemic myocardial perfusion ratio were increased in the ischemic myocardium in the MVM group compared with the CON group. Pigs in the MVM group had increased capillary and arteriolar density in the ischemic myocardial tissue compared with CON pigs. There was an increase in expression of the phospho–mitogen‐activated protein kinase/mitogen‐activated protein kinase ratio, the phospho–endothelial nitric oxide synthase/endothelial nitric oxide synthase ratio, and total protein kinase B in the MVM group compared with CON. There was an increase in cardiac output and stroke volume in the MVM group compared with CON.ConclusionsIn the setting of chronic myocardial ischemia, myocardial injection of human mesenchymal cell–derived EVs increases blood flow to ischemic myocardial tissue by induction of capillary and arteriolar growth via activation of the protein kinase B/endothelial nitric oxide synthase and mitogen‐activated protein kinase signaling pathways resulting in increased cardiac output and stroke volume.

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“…Therefore, proposed strategies to restore the damaged myocardium have focused on external interventions such as cell, tissue, or full organ replacement [24]. In contrast to other non-cardiomyogenic stem cell types such as mesenchymal precursor cells that confer benefits through paracrine effects [25], transplanted hPSC-CMs also have the potential to achieve true contractile tissue regeneration [26]. Indeed, experiments in small and large animal models have demonstrated that hPSC-CMs transplanted to sites of ischemic injury survive and can electrically couple to the host myocardium [27–35].…”

Section: Applications Of Pluripotent Stem Cell-derived Cardiomyocytesmentioning

confidence: 99%

Cryopreservation of Human Pluripotent Stem Cell-Derived Cardiomyocytes: Strategies, Challenges, and Future Directions

Preininger

Singh

2016

Advances in Experimental Medicine and Biology

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In recent years, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a vital cell source for in vitro modeling of genetic cardiovascular disorders, drug screening, and in vivo cardiac regeneration research. Looking forward, the ability to efficiently cryopreserve hPSC-CMs without compromising their normal biochemical and physiologic functions will dramatically facilitate their various biomedical applications. Although working protocols for freezing, storing, and thawing hPSC-CMs have been established, the question remains as to whether they are optimal. In this chapter, we discuss our current understanding of cryopreservation appertaining to hPSC-CMs, and proffer key questions regarding the mechanical, contractile, and regenerative properties of cryopreserved hPSC-CMs.

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The future of regenerating the myocardium

Abstract: In today's cardiovascular field, once a cardiomyocyte is lost it is lost for good, without any form of direct therapeutic option. For these reasons, cell therapy justifies our continued attention and efforts, and may constitute the holy grail of cardiovascular therapeutics.

Cited by 17 publications

References 68 publications

Bone Marrow Mesenchymal Stromal Cells Stimulate Skeletal Myoblast Proliferation through the Paracrine Release of VEGF

Bone Marrow Mesenchymal Stromal Cells Stimulate Skeletal Myoblast Proliferation through the Paracrine Release of VEGF

Extracellular Vesicle Injection Improves Myocardial Function and Increases Angiogenesis in a Swine Model of Chronic Ischemia

Cryopreservation of Human Pluripotent Stem Cell-Derived Cardiomyocytes: Strategies, Challenges, and Future Directions

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