Perspectives on Directions and Priorities for Future Preclinical Studies in Regenerative Medicine

Shamagian, Lilian Grigorian; Madonna, Rosalinda; Taylor, Doris A.; Climent, Andreu Μ.; Prósper, Felipe; Brás-Rosário, Luís; Bayés‐Genís, Antoni; Ferdinándy, Péter; Fernández‐Avilés, Francisco; Belmonte, Juan Carlos Izpisúa; Fuster, Valentín; Bolli, Roberto

doi:10.1161/circresaha.118.313795

Cited by 32 publications

(27 citation statements)

References 132 publications

(122 reference statements)

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“…However, the more important consequence of this observation is that this process mimics aspects of cardiac remodeling. Extensive cardiac remodeling with global cardiac changing in gene expression occurs subsequently to myocardial infarction (MI) when repair processes occur [13][14][15]. Therefore, in the present study we investigated the expression of swiprosin-1 in cardiac tissue during subsequent cardiac remodeling.…”

Section: Introductionmentioning

confidence: 99%

Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

Giricz

Makkos

Schreckenberg

et al. 2020

IJMS

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Swiprosin-1 (EFhD2) is a molecule that triggers structural adaptation of isolated adult rat cardiomyocytes to cell culture conditions by initiating a process known as cell spreading. This process mimics central aspects of cardiac remodeling, as it occurs subsequent to myocardial infarction. However, expression of swiprosin-1 in cardiac tissue and its regulation in vivo has not yet been addressed. The expression of swiprosin-1 was analyzed in mice, rat, and pig hearts undergoing myocardial infarction or ischemia/reperfusion with or without cardiac protection by ischemic pre- and postconditioning. In mouse hearts, swiprosin-1 protein expression was increased after 4 and 7 days in myocardial infarct areas specifically in cardiomyocytes as verified by immunoblotting and histology. In rat hearts, swiprosin-1 mRNA expression was induced within 7 days after ischemia/reperfusion but this induction was abrogated by conditioning. As in cultured cardiomyocytes, the expression of swiprosin-1 was associated with a coinduction of arrestin-2, suggesting a common mechanism of regulation. Rno-miR-32-3p and rno-miR-34c-3p were associated with the regulation pattern of both molecules. Moreover, induction of swiprosin-1 and ssc-miR-34c was also confirmed in the infarct zone of pigs. In summary, our data show that up-regulation of swiprosin-1 appears in the postischemic heart during cardiac remodeling and repair in different species.

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Section: Introductionmentioning

confidence: 99%

Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

Giricz

Makkos

Schreckenberg

et al. 2020

IJMS

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“…After two decades of intensive research in the field of cell therapy for heart disease, conclusive demonstration of therapeutic efficacy of the cells is still lacking, and a fundamental understanding of how cell therapy works is still elusive[1, 3, 4, 29-31]. This has led to discussions of changes in the field and search for new paradigms for future research.…”

Section: Discussionmentioning

confidence: 99%

“…This has led to discussions of changes in the field and search for new paradigms for future research. A paradigm of repeated dosing of cells has become one of the investigational priorities[4, 29, 32]. However, the lack of a reliable, repeatable cell delivery approach in preclinical studies using small animals hinders progress.…”

Section: Discussionmentioning

confidence: 99%

Echocardiography-guided percutaneous left ventricular intracavitary injection as a cell delivery approach in infarcted mice

Nong

Guo

Tomlin

et al. 2020

Preprint

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21Background: In the field of cell therapy for heart disease, a new paradigm of repeated 22 dosing of cells has recently emerged. However, the lack of a repeatable cell delivery 23 method in preclinical studies in rodents is a major obstacle to investigating this 24 paradigm. 25 Methods and Results:We have established and standardized a method of 26 echocardiography-guided percutaneous left ventricular intracavitary injection (echo-27 guided LV injection) as a cell delivery approach in infarcted mice. Here, we describe the 28 method in detail and address several important issues regarding it. First, by integrating 29 anatomical and echocardiographic considerations, we have established strategies to 30 determine a safe anatomical window for injection in infarcted mice. Second, we 31 summarize our experience with this method (734 injections). The overall survival rate 32 was 91.4%. Previous studies results suggest that 1×10 6 cells delivered via this method 33 yielded similar retention in the heart at 24 h as 1×10 5 cells delivered via intracoronary or 34 intramyocardial injection. Lastly, we examined the efficacy of this cell delivery approach. 35Compared with vehicle treatment, cardiac mesenchymal cells (CMCs) delivered via this 36 method improved cardiac function assessed both echocardiographically and 37 hemodynamically. Furthermore, repeated injections of CMCs via this method yielded 38 greater cardiac function improvement than single dose administration. 39 Conclusion: Echo-guided LV injection is a feasible, reproducible, relatively less 40 invasive and effective delivery method for cell therapy in heart disease. It is an 41 important approach that could move the field of cell therapy forward, especially with 42 regard to repeated cell administrations. 43 44 Introduction 45 Despite two decades of intensive research in cell therapy for heart disease, the optimal 46 cell type, dosage, delivery method and frequency are still elusive, as is the mechanism 47 behind the observed cardiac benefits of cell therapy[1, 2]. The available evidence 48 supports two fundamental concepts: i) the majority of cell-related effects do not result 49 from direct cardiomyocyte differentiation but rather from paracrine mechanisms[3], ii) all 50 cells, regardless of cell type or delivery approach, fail to engraft in the heart to a 51 significant extent[4]. Therefore, expecting a single administration of short-lasting cells to 52 produce long-term benefits may be unrealistic. A paradigm shift from single 53 administration to repeated administrations of cells is underway[1, 3-5]. 54 Typical cell delivery approaches in clinical studies include intracoronary infusion, 55 transendocardial injection, and direct epicardial injection[1, 2]. The first two are catheter-56 based, and can be repeated without opening the chest although it would be practically 57 difficult to perform repeated catheter-based deliveries in humans. However, in 58 preclinical studies in rodents, repeated cell administrations can be difficult to perform. 59 Most cell...

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“…The biomechanical properties of naturally regenerated LV muscle after MI have not been thoroughly examined. Because MI injury significantly disrupts global tissue architecture 15 , confirmation is needed that the regenerated cardiac muscle is mechanically integrated such that tissue-level biomechanical properties are optimally maintained 23 . A previous study employed a cryoinjury model in adult zebrafish, and demonstrated using micropipette aspiration that while the injured myocardium stiffened acutely after sustaining damage, myocardial biomechanics fully normalized by 5 weeks after injury in association with complete natural cardiac regeneration 24 .…”

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confidence: 99%

Multiaxial Lenticular Stress-Strain Relationship of Native Myocardium is Preserved by Infarct-Induced Natural Heart Regeneration in Neonatal Mice

Wang

Bennett-Kennett

Paulsen

et al. 2020

Sci Rep

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neonatal mice exhibit natural heart regeneration after myocardial infarction (Mi) on postnatal day 1 (P1), but this ability is lost by postnatal day 7 (P7). Cardiac biomechanics intricately affect longterm heart function, but whether regenerated cardiac muscle is biomechanically similar to native myocardium remains unknown. We hypothesized that neonatal heart regeneration preserves native left ventricular (LV) biomechanical properties after MI. C57BL/6J mice underwent sham surgery or left anterior descending coronary artery ligation at age P1 or P7. Echocardiography performed 4 weeks post-MI showed that P1 MI and sham mice (n = 22, each) had similar LV wall thickness, diameter, and ejection fraction (59.6% vs 60.7%, p = 0.6514). Compared to P7 shams (n = 20), P7 MI mice (n = 20) had significant LV wall thinning, chamber enlargement, and depressed ejection fraction (32.6% vs 61.8%, p < 0.0001). Afterward, the LV was explanted and pressurized ex vivo, and the multiaxial lenticular stress-strain relationship was tracked. While LV tissue modulus for P1 MI and sham mice were similar (341.9 kPa vs 363.4 kPa, p = 0.6140), the modulus for P7 MI mice was significantly greater than that for P7 shams (691.6 kPa vs 429.2 kPa, p = 0.0194). We conclude that, in neonatal mice, regenerated LV muscle has similar biomechanical properties as native LV myocardium.

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Perspectives on Directions and Priorities for Future Preclinical Studies in Regenerative Medicine

Cited by 32 publications

References 132 publications

Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

Echocardiography-guided percutaneous left ventricular intracavitary injection as a cell delivery approach in infarcted mice

Multiaxial Lenticular Stress-Strain Relationship of Native Myocardium is Preserved by Infarct-Induced Natural Heart Regeneration in Neonatal Mice

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