Calcium dependent CAMTA1 in adult stem cell commitment to a myocardial lineage.


The phenotype of somatic cells has recently been found to be reversible. Direct reprogramming of one cell type into another has been achieved with transduction and over expression of exogenous defined transcription factors emphasizing their role in specifying cell fate. To discover early and novel endogenous transcription factors that may have a role in adult-derived stem cell acquisition of a cardiomyocyte phenotype, mesenchymal stem cells from human and mouse bone marrow and rat liver were co-cultured with neonatal cardiomyocytes as an in vitro cardiogenic microenvironment. Cell-cell communications develop between the two cell types as early as 24 hrs in co-culture and are required for elaboration of a myocardial phenotype in the stem cells 8-16 days later. These intercellular communications are associated with novel Ca(2+) oscillations in the stem cells that are synchronous with the Ca(2+) transients in adjacent cardiomyocytes and are detected in the stem cells as early as 24-48 hrs in co-culture. Early and significant up-regulation of Ca(2+)-dependent effectors, CAMTA1 and RCAN1 ensues before a myocardial program is activated. CAMTA1 loss-of-function minimizes the activation of the cardiac gene program in the stem cells. While the expression of RCAN1 suggests involvement of the well-characterized calcineurin-NFAT pathway as a response to a Ca(2+) signal, the CAMTA1 up-regulated expression as a response to such a signal in the stem cells was unknown. Cell-cell communications between the stem cells and adjacent cardiomyocytes induce Ca(2+) signals that activate a myocardial gene program in the stem cells via a novel and early Ca(2+)-dependent intermediate, up-regulation of CAMTA1.





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Publication Info

Muller-Borer, Barbara, Gwyn Esch, Rob Aldina, Woohyun Woon, Raymond Fox, Nenad Bursac, Sylvia Hiller, Nobuyuo Maeda, et al. (2012). Calcium dependent CAMTA1 in adult stem cell commitment to a myocardial lineage. PLoS One, 7(6). p. e38454. 10.1371/journal.pone.0038454 Retrieved from

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Nenad Bursac

Professor of Biomedical Engineering

Bursac's research interests include: Stem cell, tissue engineering, and gene based therapies for heart and muscle regeneration; Cardiac electrophysiology and arrhythmias; Organ-on-chip and tissue engineering technologies for disease modeling and therapeutic screening; Small and large animal models of heart and muscle injury, disease, and regeneration.

The focus of my research is on application of pluripotent stem cells, tissue engineering, and gene therapy technologies for: 1) basic studies of striated muscle biology and disease in vitro and 2) regenerative therapies in small and large animal models in vivo. For in vitro studies, micropatterning of extracellular matrix proteins or protein hydrogels and 3D cell culture are used to engineer rodent and human striated muscle tissues that replicate the structure-function relationships present in healthy and diseased muscles. We use these models to separate and systematically study the roles of structural and genetic factors that contribute cardiac and skeletal muscle function and disease at multiple organizational levels, from single cells to tissues. Combining cardiac and skeletal muscle cells with primary or iPSC-derived non-muscle cells (endothelial cells, smooth muscle cells, immune system cells, neurons) allows us to generate more realistic models of healthy and diseased human tissues and utilize them to mechanistically study molecular and cellular processes of tissue injury, vascularization, innervation, electromechanical integration, fibrosis, and functional repair. Currently, in vitro models of Duchenne Muscular Dystrophy, Pompe disease, dyspherlinopathies, and various cardiomyopathies are studied in the lab. For in vivo studies, we employ rodent models of volumetric skeletal muscle loss, cardiotoxin and BaCl2 injury as well as myocardial infarction and transverse aortic constriction to study how cell, tissue engineering, and gene (viral) therapies can lead to safe and efficient tissue repair and regeneration. In large animal (porcine) models of myocardial injury and arrhythmias, we are exploring how human iPSC derived heart tissue patches and application of engineered ion channels can improve cardiac function and prevent heart failure or sudden cardiac death.



Mary Redmond Hutson

Assistant Professor of Pediatrics

My laboratory is interested in understanding how congenital heart defects occur. In particular I am focused on defects of the conotruncus (or arterial pole) which include persistent truncus arteriosus, double outlet right ventricle, and tetralogy of Fallot. During early stages of heart development the secondary heart field, a population of cardiac stem cells, forms the smooth muscle and myocardial junction of the arterial pole. Another cell population important for arterial pole formation are the cardiac neural crest. These cells migrate into the arterial pole and form a septum to divide the systemic and pulmonary circulations. Disruption of secondary heart field or cardiac neural crest development results in conotruncal defects. My research focuses on the understanding the integration of the cell signaling mechanisms that influence the secondary heart field progenitor cells and cardiac neural crest to form the arterial pole. We have shown that modulation of fibroblast growth factor 8 (FGF8) signaling by cardiac neural crest in the pharynx is required for normal heart development and that too much or too little FGF8 signaling results in secondary heart field defects that lead to arterial pole defects. Current work in the lab focuses on the integration of FGF8 signaling with other signaling pathways including retinoic acid, sonic hedgehog (Shh), and BMP to effect normal arterial pole development. We want to understand how these signals balance to maintain a pool of undifferentiated secondary heart field progenitors and the coordinated differentiation of myocardial and vascular smooth muscle cells.

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