‘Shovel-Ready’ applications of stem cell advances for pediatric heart disease

Files, Matthew D.; Boucek, Robert J.

doi:10.1097/mop.0b013e328357a4cf

Cited by 10 publications

(25 citation statements)

References 51 publications

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“…Unlike hypertrophic cardiomyopathy and congenital arrhythmias, both of which have been shown to recapitulate the disease phenotype in iPSC models [ 41 , 42 ], CM function in most critical CHD patients is believed to be intrinsically normal in the majority of cases, suggesting that most cases of CHD‐associated heart failure may be amenable to autologous cell therapy. Additionally, because amniotic fluid and AF‐iPSCs cells can be easily banked, our approach is highly scalable and not limited by cell scarcity for most perinatal applications, including the study of 3D microtissue formation, as well as the delivery of AF‐CMs to rescue heart failure or augment existing function during the initial palliative operation [ 35 , 43 – 45 ]. Assuming that adequate proliferation of AF‐iPSCs can be established and maintained in culture, this technology could also be used to seed an entire decellularized heart with CMs in time for implantation during early infancy [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Human Cardiomyocytes Prior to Birth by Integration-Free Reprogramming of Amniotic Fluid Cells

Jiang

Herron

Bernardo

et al. 2016

Stem Cells Translational Medicine

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The establishment of an abundant source of autologous cardiac progenitor cells would represent a major advance toward eventual clinical translation of regenerative medicine strategies in children with prenatally diagnosed congenital heart disease. In support of this concept, we sought to examine whether functional, transgene-free human cardiomyocytes (CMs) with potential for patient-specific and autologous applications could be reliably generated following routine amniocentesis. Under institutional review board approval, amniotic fluid specimens (8-10 ml) at 20 weeks gestation were expanded and reprogrammed toward pluripotency using nonintegrating Sendai virus (SeV) expressing OCT4, SOX2, cMYC, and KLF4. Following exposure of these induced pluripotent stem cells to cardiogenic differentiation conditions, spontaneously beating amniotic fluid-derived cardiomyocytes (AF-CMs) were successfully generated with high efficiency. After 6 weeks, quantitative gene expression revealed a mixed population of differentiated atrial, ventricular, and nodal AF-CMs, as demonstrated by upregulation of multiple cardiac markers, including MYH6, MYL7, TNNT2, TTN, and HCN4, which were comparable to levels expressed by neonatal dermal fibroblast-derived CM controls. AF-CMs had a normal karyotype and demonstrated loss of NANOG, OCT4, and the SeV transgene. Functional characterization of SIRPA + AF-CMs showed a higher spontaneous beat frequency in comparison with dermal fibroblast controls but revealed normal calcium transients and appropriate chronotropic responses after b-adrenergic agonist stimulation. Taken together, these data suggest that somatic cells present within human amniotic fluid can be used to generate a highly scalable source of functional, transgene-free, autologous CMs before a child is born. This approach may be ideally suited for patients with prenatally diagnosed cardiac anomalies. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1595-1606 SIGNIFICANCEThis study presents transgene-free human amniotic fluid-derived cardiomyocytes (AF-CMs) for potential therapy in tissue engineering and regenerative medicine applications. Using 8-10 ml of amniotic fluid harvested at 20 weeks gestation from normal pregnancies, a mixed population of atrial, ventricular, and nodal AF-CMs were reliably generated after Sendai virus reprogramming toward pluripotency. Functional characterization of purified populations of beating AF-CMs revealed normal calcium transients and appropriate chronotropic responses after b-adrenergic agonist stimulation in comparison with dermal fibroblast controls. Because AF-CMs can be generated in fewer than 16 weeks, this approach may be ideally suited for eventual clinical translation at birth in children with prenatally diagnosed cardiac anomalies.

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Section: Discussionmentioning

confidence: 99%

Human Cardiomyocytes Prior to Birth by Integration-Free Reprogramming of Amniotic Fluid Cells

Jiang

Herron

Bernardo

et al. 2016

Stem Cells Translational Medicine

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“…Currently, stem cell therapy with cardiac progenitor cells (CPCs) is under evaluation in clinical trials (11). Rupp and coworkers could impressively show first results of stem cell therapy in children.…”

Section: Right Ventricular Failure In Congenital Heart Diseasementioning

confidence: 99%

Right Ventricular Failure and Pathobiology in Patients with Congenital Heart Disease – Implications for Long-Term Follow-Up

et al. 2013

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Right ventricular dysfunction represents a common problem in patients with congenital heart defects, such as Tetralogy of Fallot or pulmonary arterial hypertension. Patients with congenital heart defects may present with a pressure or volume overloaded right ventricle (RV) in a bi-ventricular heart or in a single ventricular circulation in which the RV serves as systemic ventricle. Both subsets of patients are at risk of developing right ventricular failure. Obtaining functional and morphological imaging data of the right heart is technically more difficult than imaging of the left ventricle. In contrast to findings on mechanisms of left ventricular dysfunction, very little is known about the pathophysiologic alterations of the right heart. The two main causes of right ventricular dysfunction are pressure and/or volume overload of the RV. Until now, there are no appropriate models available analyzing the effects of pressure and/or volume overload on the RV. This review intends to summarize clinical aspects mainly focusing on the current research in this field. In future, there will be increasing attention to individual care of patients with right heart diseases. Hence, further investigations are essential for understanding the right ventricular pathobiology.

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“…The candidate stem cell for transplantation must improve heart function without inducing an immune response, arrhythmias, or carcinogenesis [3]. Results of animal model studies and clinical trials suggest that transplantation of cardiac stem cells (CSCs), resident cardiac precursor cells in the heart, may be one of the best strategies to cure adult or pediatric heart diseases [4][5][6][7][8]. All CSCs populations contain most properties of stem cells: self-renewal, multi-lineage differentiation, and clonogenic potentials.…”

mentioning

confidence: 99%

Cellular and Molecular Characterization of Human Cardiac Stem Cells Reveals Key Features Essential for Their Function and Safety

Vahdat

Mousavi

Omrani

et al. 2015

Stem Cells and Development

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‘Shovel-Ready’ applications of stem cell advances for pediatric heart disease

Cited by 10 publications

References 51 publications

Human Cardiomyocytes Prior to Birth by Integration-Free Reprogramming of Amniotic Fluid Cells

Human Cardiomyocytes Prior to Birth by Integration-Free Reprogramming of Amniotic Fluid Cells

Right Ventricular Failure and Pathobiology in Patients with Congenital Heart Disease – Implications for Long-Term Follow-Up

Cellular and Molecular Characterization of Human Cardiac Stem Cells Reveals Key Features Essential for Their Function and Safety

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