Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: Three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single-Ventricle Physiology (TICAP) trial

Tarui, Suguru; Ishigami, Shuta; Ousaka, Daiki; Kasahara, Shingo; Ohtsuki, Shinichi; Sano, Shunji; Oh, Hidemasa

doi:10.1016/j.jtcvs.2015.06.076

Cited by 103 publications

(83 citation statements)

References 33 publications

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“…Initially it was thought that direct differentiation of cardiac stem cells into cardiac myocytes was responsible for improved remodeling; however, as the science progressed, it became more evident that paracrine effects play a major role in the beneficial effects observed after CPC therapy 3 . Despite the data that suggest that CPCs do not form new myocytes, clinical trials involving CPCs 4 and other cardiac-derived cells such as cardiosphere-derived cells (CDCs) 5–7 show modest benefits in the clinic. Despite the clinical advances, mechanisms for recovery are still under investigation.…”

Section: Introductionmentioning

confidence: 99%

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Agarwal

George

Bhutani

et al. 2017

Circulation Research

149

153

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Rationale Studies have demonstrated that exosomes can repair cardiac tissue post myocardial infarction (MI) and recapitulate the benefits of cellular therapy. Objective We evaluated the role of donor age and hypoxia of human pediatric cardiac progenitor cell (CPC)-derived exosomes, in a rat model of ischemia reperfusion (IR) injury. Methods and Results Human CPCs from the right atrial appendages from children of different ages undergoing cardiac surgery for congenital heart defects were isolated and cultured under hypoxic or normoxic conditions. Exosomes were isolated from the culture-conditioned media and delivered to athymic rats following IR injury. Echocardiography at day-3 post-MI suggested statistically improved function in neonatal hypoxic and neonatal normoxic groups compared to saline-treated controls. At 28 days post-MI exosomes derived from neonatal normoxia, neonatal hypoxia, infant hypoxia, and child hypoxia significantly improved cardiac function compared to saline-treated controls. Staining showed decreased fibrosis and improved angiogenesis in hypoxic groups compared to controls. Finally, using sequencing data, a computational model was generated to link microRNA levels to specific outcomes. Conclusion CPC exosomes derived from neonates improved cardiac function independent of culture oxygen levels, while CPC-exosomes from older children were not reparative unless subjected to hypoxic conditions. Cardiac functional improvements were associated with increased angiogenesis, reduced fibrosis and improved hypertrophy resulting in improved cardiac function; however, mechanisms for normoxic neonatal CPC exosomes improved function independent of those mechanisms. This is the first study of its kind demonstrating that donor age and oxygen content in the microenvironment significantly alter the efficacy of human CPC-derived exosomes.

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Section: Introductionmentioning

confidence: 99%

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Agarwal

George

Bhutani

et al. 2017

Circulation Research

149

153

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“…Importantly, CDC-treated patients showed improved somatic growth and had lower incidence of catheter intervention for collateral occlusion during the 18-month intermediate-stage of surgical palliation, when compared with controls. Additionally, a 3-year follow-up of the results of this trial showed the continuous safety and preliminary efficacy of this therapy [72]. A number of questions are raised by this first long-term observation study in children, including how single CDC transplantation could trigger such longlasting effects in patients, regardless of mechanisms of direct differentiation or paracrine-mediated effects.…”

Section: Clinical Trials Of Progenitor Cell Therapy In Congenital Heamentioning

confidence: 82%

Challenges to success in heart failure: Cardiac cell therapies in patients with heart diseases

Ito

Sano

2016

Journal of Cardiology

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Heart failure remains the leading cause of death worldwide, and is a burgeoning problem in public health due to the limited capacity of postnatal hearts to self-renew. The pathophysiological changes in injured hearts can sometimes be manifested as scar formation or myocardial degradation, rather than supplemental muscle regeneration to replenish lost tissue during the healing processes. Stem cell therapies have been investigated as a possible treatment approach for children and adults with potentially fatal cardiovascular disease that does not respond to current medical therapies. Although the heart is one of the least regenerative organs in mammals, discoveries made during the past few decades have improved our understanding of cardiac development and resident stem/progenitor pools, which may be lineage-restricted subpopulations during the post-neonatal stage of cardiac morphogenesis. Recently, investigation has specifically focused on factors that activate either endogenous progenitor cells or preexisting cardiomyocytes, to regenerate cardiovascular cells and replace the damaged heart tissues. The discovery of induced pluripotent stem cells has advanced our technological capability to direct cardiac reprogramming by essential factors that are crucial for heart field completion in each stage. Cardiac tissue engineering technology has recently shown progress in generating myocardial tissue on human native cardiac extracellular matrix scaffolds. This review summarizes recent advances in the field of cardiac cell therapies with an emphasis on cellular mechanisms, such as bone marrow stem cells and cardiac progenitor cells, which show the high potential for success in preclinical and clinical meta-analysis studies. Expanding our current understanding of mechanisms of self-renewal in the neonatal mammalian heart may lead to the development of novel cardiovascular regenerative medicines for pediatric heart diseases.

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“…Even in clinical trials, structural and functional parameters, carried out by several imaging techniques, remain as conventional endpoints. A significant part of the clinical trials do not resort to any kind of molecular monitoring [81][82][83][84]88,89,92,94] and when they do, they are limited to some conventional cardiac markers (Table 1), mainly BNP [90,96], NT-proBNP [77][78][79][80]86,87,91,93], in addition to creatine kinase [77,86,87,90,[95][96][97], troponins I [90,96,97] and T [77,80,86,87] and some inflammation markers, such as TNF-α, IL-6 [79] and C-reactive protein [77,86]. Therefore, we suggest to screen biofluids (Box 5, Fig.…”

Section: Clinical Translationmentioning

confidence: 99%

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

Trindade

Leite‐Moreira

Ferreira-Martins

et al. 2017

International Journal of Cardiology

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Today there is an increasing demand for heart transplantations for patients diagnosed with heart failure. Though, shortage of donors as well as the large number of ineligible patients hurdle such treatment option. This, in addition to the considerable number of transplant rejections, has driven the clinical research towards the field of regenerative medicine. Nonetheless, to date, several stem cell therapies tested in animal models fall by the wayside and when they meet the criteria to clinical trials, subjects often exhibit modest improvements. A main issue slowing down the admission of such therapies in the domain of human trials is the lack of protocol standardization between research groups, which hampers comparison between different approaches as well as the lack of thought regarding the clinical translation. In this sense, given the large amount of reports on stem cell therapy studies in animal models reported in the last 3 years, we sought to evaluate their advantages and limitations towards the clinical setting and provide some suggestions for the forthcoming investigations. We expect, with this review, to start a new paradigm on regenerative medicine, by evoking the debate on how to plan novel stem cell therapy studies with animal models in order to achieve more consistent scientific production and accelerate the admission of stem cell therapies in the clinical setting.

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Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: Three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single-Ventricle Physiology (TICAP) trial

Cited by 103 publications

References 33 publications

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Challenges to success in heart failure: Cardiac cell therapies in patients with heart diseases

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

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