Stem Cell Therapy for Hypoplastic Left Heart Syndrome

Bittle, Gregory J.; Morales, David L.S.; Deatrick, Kristopher B.; Parchment, Nathaniel; Saha, Progyaparamita; Mishra, Rachana; Sharma, Sudhish; Pietris, Nicholas; Vasilenko, A M; Bor, Casey; Ambastha, Chetan; Gunasekaran, Muthukumar; Li, Deqiang; Kaushal, Sunjay

doi:10.1161/circresaha.117.311206

Cited by 38 publications

(19 citation statements)

References 103 publications

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“…The identification of the molecular systems that repress cardiomyocyte proliferation will create a novel opportunity for reparative strategies. Innovative tissue engineering [ 296 ] and stem cell implantation strategies [ 297 , 298 ] are also emerging for use during congenital heart surgery. Based on the spectacular range of model systems, experimental techniques, and computational methods, it is clear that where we go from here will be both fascinating and translational for many decades to come.…”

Section: Future Horizonsmentioning

confidence: 99%

Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease

Keller

Kowalski

Tinney

et al. 2020

JCDD

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The goal of this review is to provide a broad overview of the biomechanical maturation and regulation of vertebrate cardiovascular (CV) morphogenesis and the evidence for mechanistic relationships between function and form relevant to the origins of congenital heart disease (CHD). The embryonic heart has been investigated for over a century, initially focusing on the chick embryo due to the opportunity to isolate and investigate myocardial electromechanical maturation, the ability to directly instrument and measure normal cardiac function, intervene to alter ventricular loading conditions, and then investigate changes in functional and structural maturation to deduce mechanism. The paradigm of “Develop and validate quantitative techniques, describe normal, perturb the system, describe abnormal, then deduce mechanisms” was taught to many young investigators by Dr. Edward B. Clark and then validated by a rapidly expanding number of teams dedicated to investigate CV morphogenesis, structure–function relationships, and pathogenic mechanisms of CHD. Pioneering studies using the chick embryo model rapidly expanded into a broad range of model systems, particularly the mouse and zebrafish, to investigate the interdependent genetic and biomechanical regulation of CV morphogenesis. Several central morphogenic themes have emerged. First, CV morphogenesis is inherently dependent upon the biomechanical forces that influence cell and tissue growth and remodeling. Second, embryonic CV systems dynamically adapt to changes in biomechanical loading conditions similar to mature systems. Third, biomechanical loading conditions dynamically impact and are regulated by genetic morphogenic systems. Fourth, advanced imaging techniques coupled with computational modeling provide novel insights to validate regulatory mechanisms. Finally, insights regarding the genetic and biomechanical regulation of CV morphogenesis and adaptation are relevant to current regenerative strategies for patients with CHD.

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Section: Future Horizonsmentioning

confidence: 99%

Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease

Keller

Kowalski

Tinney

et al. 2020

JCDD

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“…Even after successful completion of surgical palliation, significant morbidity occurs due to progressive RV dysfunction 71 . HLHS patients with RV dysfunction after a Norwood procedure have an 18-month survival rate of 35% compared with a 70% survival rate for patients with normal RV function 27 .…”

Section: Reviewmentioning

confidence: 99%

“…Clinical trials for stem cell therapy in CHD are mostly carried out in patients with single ventricle circulation, as can occur with HLHS. Published ongoing studies use different stem cell types, evaluate different patient populations, and differ in the route of stem cell administration 71 , 80 , 81 , 82 , 83 , 84 . However, all have the same goal, namely to improve RV performance 71 .…”

Section: Reviewmentioning

confidence: 99%

“…Published ongoing studies use different stem cell types, evaluate different patient populations, and differ in the route of stem cell administration 71 , 80 , 81 , 82 , 83 , 84 . However, all have the same goal, namely to improve RV performance 71 . Ishigami et al reported on the first phase I clinical trial (TICAP trial: transcoronary infusion of cardiac progenitor cells in patients with single ventricle physiology, NCT01273857) 80 .…”

Section: Reviewmentioning

confidence: 99%

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New Aspects in the Diagnosis and Therapy of Fetal Hypoplastic Left Heart Syndrome

Graupner

Enzensberger

Axt-Fliedner

2019

Geburtshilfe Frauenheilkd

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Fetal hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with a lethal prognosis without postnatal therapeutic intervention or surgery. The aim of this article is to give a brief overview of new findings in the field of prenatal diagnosis and the therapy of HLHS. As cardiac output in HLHS children depends on the right ventricle (RV), prenatal assessment of fetal RV function is of interest to predict poor functional RV status before the RV becomes the systemic ventricle. Prenatal cardiac interventions such as fetal aortic valvuloplasty and non-invasive procedures such as maternal hyperoxygenation seem to be promising treatment options but will need to be evaluated with regard to long-term outcomes. Novel approaches such as stem cell therapy or neuroprotection provide important clues about the complexity of the disease. New aspects in diagnostics and therapy of HLHS show the potential of a targeted prenatal treatment planning. This could be used to optimize parental counseling as well as pre- and postnatal management of affected children.

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“…The uses for MSCs are not only limited to tissue engineering, but also include utilization of reparative and immunomodulatory properties in wound healing and realignment of dysregulated immune systems (4). Recently, there have been many publications regarding MSC biology and clinical application, and to date, 32 clinical trials have been undertaken using MSCs to treat a variety of adult heart conditions, including acute myocardial infarction, ischemic cardiomyopathy, and nonischemic dilated cardiomyopathy (5). For an adult, 1.8 ϫ 10 8 cells are typically required for cell therapy, or based on body weight, the number of required cells may be calculated as 6.64 ϫ 10 6 cells/kg (3).…”

mentioning

confidence: 99%

The extracellular domain of epithelial cell adhesion molecule (EpCAM) enhances multipotency of mesenchymal stem cells through EGFR–LIN28–LET7 signaling

Kuan

Lee

Chen

et al. 2019

Journal of Biological Chemistry

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Edited by Xiao-Fan Wang Mesenchymal stem cells (MSCs) are widely considered to be an attractive cell source for regenerative therapies, but maintaining multipotency and self-renewal in cultured MSCs is especially challenging. Hence, the development and mechanistic description of strategies that help promote multipotency in MSCs will be vital to future clinical use. Here, using an array of techniques and approaches, including cell biology, RT-quantitative PCR, immunoblotting, immunofluorescence, flow cytometry, and ChIP assays, we show that the extracellular domain of epithelial cell adhesion molecule (EpCAM) (EpEX) significantly increases the levels of pluripotency factors through a signaling cascade that includes epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and Lin-28 homolog A (LIN28) and enhances the proliferation of human bone marrow MSCs. Moreover, we found that EpEXinduced LIN28 expression reduces the expression of the microRNA LET7 and up-regulates that of the transcription factor high-mobility group AT-hook 2 (HMGA2), which activates the transcription of pluripotency factors. Surprisingly, we found that EpEX treatment also enhances osteogenesis of MSCs under differentiation conditions, as evidenced by increases in osteogenic markers, including Runt-related transcription factor 2 (RUNX2). Taken together, our results indicate that EpEX stimulates EGFR signaling and thereby context-dependently controls MSC states and activities, promoting cell proliferation and multipotency under maintenance conditions and osteogenesis under differentiation conditions.

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Stem Cell Therapy for Hypoplastic Left Heart Syndrome

Cited by 38 publications

References 103 publications

Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease

Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease

New Aspects in the Diagnosis and Therapy of Fetal Hypoplastic Left Heart Syndrome

The extracellular domain of epithelial cell adhesion molecule (EpCAM) enhances multipotency of mesenchymal stem cells through EGFR–LIN28–LET7 signaling

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