Although the beneficial effects of cellular therapy in hearts with post myocardial infarction LV remodeling (MI) have been reported recently, there could be additional benefit in applying a prefabricated cardiac muscle tissue equivalent over the surface of myocardial infarct.
We aim to develop a """"""""cardiac muscle patch"""""""", formed by entrapping human cardiac myocytes, endothelial cells and smooth muscle cells that derived from human induced pluripotent stem cells (hiPSC) in a 3D porous fibrin biomaterial. A """"""""cardiac muscle patch"""""""" could effectively prevent LV infarct scar bulging, reduce the BZ wall stress and improve the myocardial bioenergetics. One of the most significant problems in cardiovascular physiology is how the rate of ATP production and utilization is regulated in the in vivo heart and how the limitation of this rate may contribute to contractile dysfunction in failing hearts. The accurate evaluation of myocardial ATP turnover rates (ADP+Pi ?ATP), has generally not been successful because the level of myocardial free inorganic phosphate (Pi) in the in vivo heart is too low to be measured directly.
We aim to demonstrate a novel double saturation transfer (MRS-MST) method enabling us to calculate the ATP hydrolysis rate without measuring Pi levels, which overcomes the primary barrier in determining the ATP turnover rate in vivo. Although reports of human brain function imaging at high field (>7Tesla, [T]), have generated significant novel findings that advance the field of neuroscience, cardiac MRI and spectroscopy for humans at 7T is nonexistent because of the lack of coil engineering.
The specific aims (SA) are: SA1. To fabricate and characterize the human cardiac muscle patch (hcMP). We will differentiate human induced pluripotent stem cells (hiPSC) into cardiomyocytes (CM), endothelial cells (EC), and smooth muscle cells (SMC);and use these cardiac cells to fabricate an hcMP and characterize the mechanical properties of the hcMP during baseline and in response to pacing. SA2. To examine novel delivery of CM-, EC- and SMC-hiPSC for myocardial repair using an immuno-suppressed swine model of post infarction LV remodeling. We will examine whether the transplantation of a prefabricated hcMP will result in reductions in LV scar bulging and wall stress, and improvements in myocardial bioenergetics and contractile function. We will also compare the electrical stability of hearts with or without C transplantation by using a Loop Recorder to monitor EKGs 24/7 for 8 weeks, and by conducting a PES study. SA3.To examine myocardial bioenergetics in a high field magnet with previously unattainable levels of capability, sensitivity and spatial localization. 3a) To demonstrate a novel NMR MRS-MST technology that can measure the myocardial ATP turnover rate in the in vivo heart. 3b) To develop the first body coil for a 7T/125 CM large-bore magnet that can be used to perform 1H- and 31P- cardiac NMR studies for measurements of myocardial function, perfusion, and ATP turnover rate;The success of this coil will enable these methods to be readily applied in a clinical setting and provide an entirely new and valuable method for monitoring myocardial function, metabolism, and perfusion in the human heart.
We aim to develop a cardiac muscle patch, formed by entrapping human cardiac myocytes, endothelial cells and smooth muscle cells that derived from human induced pluripotent stem cells (hiPSC) in a 3D porous fibrin biomaterial. The accurate evaluation of myocardial ATP turnover rates (ADP+Pi?ATP), has generally not been successful because the level of myocardial free inorganic phosphate (Pi) in the in vivo heart is too low to be measured directly. We aim to demonstrate a novel double saturation transfer (MRS-MST) method enabling us to calculate the ATP hydrolysis rate without measuring Pi levels, which overcomes one of the most significant problems in cardiovascular physiology: measure the rate of ATP turnover in vivo. We will develop new NMR technologies to achieve previously unattainable levels of capability, sensitivity and spatial localization for cardiac imaging and spectroscopy noninvasively in a 7 T large bore magnet. Once this new NMR technology has been tested and validated in our porcine model, the identical method can be readily applied to the clinical situation
|Yang, Libang; Geng, Zhaohui; Nickel, Thomas et al. (2016) Differentiation of Human Induced-Pluripotent Stem Cells into Smooth-Muscle Cells: Two Novel Protocols. PLoS One 11:e0147155|
|Ogle, Brenda M; Bursac, Nenad; Domian, Ibrahim et al. (2016) Distilling complexity to advance cardiac tissue engineering. Sci Transl Med 8:342ps13|
|Wang, Xinhong; Liu, Junxu; Jiang, Li et al. (2016) Bach1 Induces Endothelial Cell Apoptosis and Cell-Cycle Arrest through ROS Generation. Oxid Med Cell Longev 2016:6234043|
|Jameel, Mohammad N; Xiong, Qiang; Mansoor, Abdul et al. (2016) ATP sensitive K(+) channels are critical for maintaining myocardial perfusion and high energy phosphates in the failing heart. J Mol Cell Cardiol 92:116-21|
|Jang, Albert; Xiong, Qiang; Zhang, Pengyuan et al. (2016) Transmurally differentiated measurement of ATP hydrolysis rates in the in vivo porcine hearts. Magn Reson Med 75:1859-66|
|Zhang, Liying; Guo, Jing; Zhang, Pengyuan et al. (2015) Derivation and high engraftment of patient-specific cardiomyocyte sheet using induced pluripotent stem cells generated from adult cardiac fibroblast. Circ Heart Fail 8:156-66|
|Chen, Yong; Ye, Lei; Zhong, Jia et al. (2015) The Structural Basis of Functional Improvement in Response to Human Umbilical Cord Blood Stem Cell Transplantation in Hearts With Postinfarct LV Remodeling. Cell Transplant 24:971-83|
|Kwong, Jennifer Q; Lu, Xiyuan; Correll, Robert N et al. (2015) The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart. Cell Rep 12:15-22|
|Ye, Lei; Basu, Joydeep; Zhang, Jianyi (2015) Fabrication of a myocardial patch with cells differentiated from human-induced pluripotent stem cells. Methods Mol Biol 1299:103-14|
|Cui, Weina; Jang, Albert; Zhang, Pengyuan et al. (2015) Early Detection of Myocardial Bioenergetic Deficits: A 9.4 Tesla Complete Non Invasive 31P MR Spectroscopy Study in Mice with Muscular Dystrophy. PLoS One 10:e0135000|
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