scholarly journals In vitro functional comparison of therapeutically relevant human vasculogenic progenitor cells used for cardiac cell therapy

2010 ◽  
Vol 140 (1) ◽  
pp. 216-224.e4 ◽  
Author(s):  
Yan Zhang ◽  
Serena Wong ◽  
Jessica Laflèche ◽  
Suzanne Crowe ◽  
Thierry G. Mesana ◽  
...  
2016 ◽  
Vol 213 (3) ◽  
pp. 2133OIA11
Author(s):  
Yvonne Aratyn-Schaus ◽  
Francesco S. Pasqualini ◽  
Hongyan Yuan ◽  
Megan L. McCain ◽  
George J.C. Ye ◽  
...  

2016 ◽  
Vol 212 (4) ◽  
pp. 389-397 ◽  
Author(s):  
Yvonne Aratyn-Schaus ◽  
Francesco S. Pasqualini ◽  
Hongyan Yuan ◽  
Megan L. McCain ◽  
George J.C. Ye ◽  
...  

The efficacy of cardiac cell therapy depends on the integration of existing and newly formed cardiomyocytes. Here, we developed a minimal in vitro model of this interface by engineering two cell microtissues (μtissues) containing mouse cardiomyocytes, representing spared myocardium after injury, and cardiomyocytes generated from embryonic and induced pluripotent stem cells, to model newly formed cells. We demonstrated that weaker stem cell–derived myocytes coupled with stronger myocytes to support synchronous contraction, but this arrangement required focal adhesion-like structures near the cell–cell junction that degrade force transmission between cells. Moreover, we developed a computational model of μtissue mechanics to demonstrate that a reduction in isometric tension is sufficient to impair force transmission across the cell–cell boundary. Together, our in vitro and in silico results suggest that mechanotransductive mechanisms may contribute to the modest functional benefits observed in cell-therapy studies by regulating the amount of contractile force effectively transmitted at the junction between newly formed and spared myocytes.


2017 ◽  
Vol 66 (01) ◽  
pp. 042-052 ◽  
Author(s):  
Timo Nazari-Shafti ◽  
Jörg Kempfert ◽  
Volkmar Falk ◽  
Wilhelm Röll ◽  
Christof Stamm

AbstractPreclinical data suggested that somatic stem or progenitor cells derived induce and/or support endogenous repair mechanisms of the myocardium. Such cell populations were clearly shown to promote neovascularization in postischemic tissue, and some evidence also indicated transdifferentiation into cardiomyocytes. In the clinical setting, however, many attempts to regenerate damaged myocardium with a variety of autologous and allogeneic somatic progenitors have failed to generate the expected therapeutic efficacy. Currently, efforts are being made to select specific cellular subpopulations, modify somatic cells to augment their regenerative capacity, improve delivery methods, and develop markers selection of potentially responding patients. Cardiac surgical groups have pioneered and continue to advance the field of cellular therapies. While the initial excitement has subsided, the field has evolved into one of the pillars of surgical research and benefits from novel methods such as cellular reprogramming, genetic modification, and pluripotent stem cell technology. This review highlights developments and controversies in somatic cardiac cell therapy and provides a comprehensive overview of completed and ongoing clinical trials.


Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Tatsuya Aonuma ◽  
Naofumi Takehara ◽  
Keisuke Maruyama ◽  
Maki Kabara ◽  
Motoki Matsuki ◽  
...  

Introduction: Overcoming the poor survival of cell grafts is an indispensable mission in cell therapy. Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1) is known as a multifunctional enzyme to encourage cell survival, whereas the role of APE1 in cardiac cell therapy is still unknown. Hypothesis: APE1 overexpression in cardiac progenitor cells (CPC) ameliorates the effect of cardiac cell therapy. Methods: CPCs from 8-10 week-old C57BL/6 mice hearts were transfected with APE1-DsRed gene (APE1-CPC) or DsRed gene (Control [Ct]-CPC). The apoptosis induced by oxidative stress was assessed in APE1-/Ct-CPCs, and in neonatal rat cardiomyocytes (NRCM) within the co-culture system of APE1-/Ct-CPCs. Western blot analysis indicated the cellular signal to protect CPC via APE1 enzyme. To evaluate the effect of APE1 overexpression in cell therapy, we transplanted APE1-CPCs and Ct-CPCs into the mice myocardial infarction (MI) model and assessed the pathophysiological role of APE1 with functional and histological analysis. Results: Under the oxidative stress condition, APE1 overexpression inhibited the apoptosis of CPCs and accelerated TAK1 activation (Ct-CPC : APE1-CPC = 1.5±0.4 : 3.3±1.6 fold, p<0.05), and consequently NfKB phosphorylation in CPCs. In the co-culture system, the apoptosis of NRCMs was inhibited with APE1-CPCs compared to that with Ct-CPCs. In vivo, in the mice MI model, the number of total CPC grafts and cardiac α-actinin-positive graft CPCs were significantly larger in APE1-CPC injected mice (APE1 mice) compared to Ct-CPC injected mice (Ct mice) at 7 days after implantation. Eventually, the left ventricular ejection fraction of APE1 mice was significantly improved compared to Ct mice (Ct mice : APE1 mice = +3.1±6.7 : +11.3±4.0%, p<0.05) and was accompanied with the attenuation of fibrosis at 28 days after implantation. Conclusions: APE1 gene inhibited the apoptosis of CPCs and host cells against oxidative stress via the activation of TAK1-NFkB pathway, which is a novel insight into the stress response of APE1 enzyme. Furthermore, APE1-CPC grafts that effectively survived in the ischemic heart restored cardiac dysfunction and attenuated myocardial infarct size, and may be an innovative strategy to reinforce cardiac cell therapy.


2016 ◽  
Vol 147 (3) ◽  
pp. 1473OIA17
Author(s):  
Yvonne Aratyn-Schaus ◽  
Francesco S. Pasqualini ◽  
Hongyan Yuan ◽  
Megan L. McCain ◽  
George J.C. Ye ◽  
...  

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Francesco S Pasqualini ◽  
Yvonne Aratyn-Schaus ◽  
Hongyan Yuan ◽  
Megan L McCain ◽  
George J Ye ◽  
...  

For cardiac cell therapy to be effective, newly formed immature cardiomyocytes need to structurally and functionally integrate with the existing myocardium. Unfortunately, testing the electro-chemo-mechanical coupling of mature and immature cardiomyocytes in vivo is difficult. Here we engineered two cell μtissues containing combinations of mouse neonate, ES-derived, and iPS-derived cardiac myocytes on flexible substrates and utilized ratiometric calcium detection and traction force microscopy to measure excitation-contraction coupling in individual cells and in the pairs. We found that SC-derived cardiac myocytes can structurally couple with neonate cardiomyocytes to functionally support synchronous contraction, yet diastolic calcium levels were reduced in SC-derived cardiomyocytes. Consistently, neonate cardiomyocytes exerted peak systolic forces that were ~1.5-fold higher than that generated by SC-derived myocytes, yielding an imbalance in tension within the pair that was dissipated by focal adhesion-like structures at the cell-cell boundary. Finally we developed a finite element model of two-cell tissue contraction to demonstrate that an imbalance in isometric tension is sufficient to limit force transmission across cell-cell boundaries. Taken together, these results suggest that reduced force transmission between poorly coupled immature and native cardiomyocytes may explain the incomplete repair of ejection fraction observed in several clinical studies of cardiac cell therapy.


2010 ◽  
Vol 58 (S 01) ◽  
Author(s):  
B Nasseri ◽  
M Kukucka ◽  
SJ Kim ◽  
YH Choi ◽  
KS Kang ◽  
...  

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