Programming and Isolation of Highly Pure Physiologically and Pharmacologically Functional Sinus-Nodal Bodies from Pluripotent Stem Cells

Jung, Julia Jeannine; Husse, Britta; Rimmbach, Christian; Krebs, Stefan; Stieber, Juliane; Steinhoff, Gustav; Dendorfer, Andreas; Franz, Wolfgang-Michael; Dávid, Róbert

doi:10.1016/j.stemcr.2014.03.006

Cited by 79 publications

(96 citation statements)

References 36 publications

(33 reference statements)

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“…These do not necessarily reflect stem cell populations with high potential to regenerate myocardium, however [7]. Accordingly, pluripotent stem cells have been intensively investigated as a source for the generation of cardiomyocytes [8], cells of the conduction system [9] or cardiovascular progenitors [10]. Clinical translation of these highly advanced cell products requires new methods for appropriate safety and efficacy testing with regard to application in patients.…”

Section: Introductionmentioning

confidence: 99%

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Lang

Wolfien

Langenbach

et al. 2017

Cell Physiol Biochem

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Aims: Stem cell-based regenerative therapies for the treatment of ischemic myocardium are currently a subject of intensive investigation. A variety of cell populations have been demonstrated to be safe and to exert some positive effects in human Phase I and II clinical trials, however conclusive evidence of efficacy is still lacking. While the relevance of animal models for appropriate pre-clinical safety and efficacy testing with regard to application in Phase III studies continues to increase, concerns have been expressed regarding the validity of the mouse model to predict clinical results. Against the background that hundreds of preclinical studies have assessed the efficacy of numerous kinds of cell preparations - including pluripotent stem cells - for cardiac repair, we undertook a systematic re-evaluation of data from the mouse model, which initially paved the way for the first clinical trials in this field. Methods and Results: A systematic literature screen was performed to identify publications reporting results of cardiac stem cell therapies for the treatment of myocardial ischemia in the mouse model. Only peer-reviewed and placebo-controlled studies using magnet resonance imaging (MRI) for left ventricular ejection fraction (LVEF) assessment were included. Experimental data from 21 studies involving 583 animals demonstrate a significant improvement in LVEF of 8.59%+/- 2.36; p=.012 (95% CI, 3.7–13.8) compared with control animals. Conclusion: The mouse is a valid model to evaluate the efficacy of cell-based advanced therapies for the treatment of ischemic myocardial damage. Further studies are required to understand the mechanisms underlying stem cell based improvement of cardiac function after ischemia.

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Section: Introductionmentioning

confidence: 99%

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Lang

Wolfien

Langenbach

et al. 2017

Cell Physiol Biochem

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“…In contrast, our protocol leads to cells that do not only exhibit electrical oscillations but also the subtle electrophysiological and calcium signaling characteristics as well as distinctive morphological features of endogenous pacemaker cells 7 . This technology may become an important prerequisite for alternatives to electronic pacing devices.…”

Section: Representative Resultsmentioning

confidence: 95%

“…Under Isoprenaline administration even beating frequencies of 550 bpm are achieved. Notably, iSABs consist of over 80% functional nodal cells as evident from extensive physiological analyses 7 . Recently, several approaches to generate sinus nodal cells using direct reprogramming 19 , surface markers 14 or pharmacological treatment with small molecules 16,17 were described.…”

mentioning

confidence: 99%

Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection

Rimmbach

Jung

Dávid

2015

JoVE

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Treatment of the "sick sinus syndrome" is based on artificial pacemakers. These bear hazards such as battery failure and infections. Moreover, they lack hormone responsiveness and the overall procedure is cost-intensive. "Biological pacemakers" generated from PSCs may become an alternative, yet the typical content of pacemaker cells in Embryoid Bodies (EBs) is extremely low. The described protocol combines "forward programming" of murine PSCs via the sinus node inducer TBX3 with Myh6-promoter based antibiotic selection. This yields cardiomyocyte aggregates consistent of >80% physiologically functional pacemaker cells. These "induced-sinoatrial-bodies" ("iSABs") are spontaneously contracting at yet unreached frequencies (400-500 bpm) corresponding to nodal cells isolated from mouse hearts and are able to pace murine myocardium ex vivo. Using the described protocol highly pure sinus nodal single cells can be generated which e.g. can be used for in vitro drug testing. Furthermore, the iSABs generated according to this protocol may become a crucial step towards heart tissue engineering. Video LinkThe video component of this article can be found at

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“…Considerable efforts are being directed at trying to differentiate PSCs to pacemaker cells, for disease modelling purposes and also with the intention of making biological pacemakers in the future. Promising results have been shown through genetic means by overexpressing transcription factors important in SAN development, namely Tbx3 and Shox2 during mouse ESC differentiation (Ionta et al, (2015); Jung et al, 2014). In hESCs, inhibition of neuregulin (NRG)-1β/ErbB signalling was shown to promote the differentiation of nodal-type cells and inhibit induction of workingtype cardiomyocytes (Zhu et al, 2010).…”

Section: Cardiomyocyte Subtype Specification Through Cpc Patterningmentioning

confidence: 99%

Pluripotent stem cell derived cardiovascular progenitors – A developmental perspective

Birket

Mummery

2015

Developmental Biology

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Human pluripotent stem cells can now be routinely differentiated into cardiac cell types including contractile cardiomyocytes, enabling the study of heart development and disease in vitro, and creating opportunities for the development of novel therapeutic interventions for patients. Our grasp of the system, however, remains partial, and a significant reason for this has been our inability to effectively purify and expand the intermediate cardiovascular progenitor cells (CPCs) equivalent to those studied in heart development. Doing so could facilitate the construction of a cardiac lineage cell fate map, boosting our capacity to more finely control stem cell lineage commitment to functionally distinct cardiac identities, as well as providing a model for identifying which genes confer cardiac potential on CPCs. This review offers a perspective on CPC development as understood from model organisms and pluripotent stem cell systems, focusing on issues of identity as well as the signalling implicated in inducing, expanding and patterning these cells.

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Programming and Isolation of Highly Pure Physiologically and Pharmacologically Functional Sinus-Nodal Bodies from Pluripotent Stem Cells

Cited by 79 publications

References 36 publications

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection

Pluripotent stem cell derived cardiovascular progenitors – A developmental perspective

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