Myocardial ischemia, infarction, and heart failure constitute a disease spectrum which israpidly becoming one of the foremost global health challenges. Current therapies focus uponpharmacologic optimization and macrorevascularization via PCI and CABG. Reconstructiveand replacement therapies are limited in applicability or availability. A significant unmet need isthat of microrevascularization. Repeated studies have demonstrated survival advantage inpatients with robust collateralization. Thus the presence of endogenous revascularization andrepair mechanisms exist and the benefits are clear; but the native potency is generallyinadequate. In the initial funding period, we studied the primary effectors of endogenousmicrorevascularization, endothelial progenitor stem cells (EPC) and their potent chemokinestromal cell derived factor 1-alpha(SDF). We were able to significantly augment microvascularangiogenesis and improve local tissue biomechanical properties, ventricular geometry andcardiac function after myocardial ischemic injury. Via computational protein engineering, wethen designed and synthesized a supra-efficient SDF analog as well as constructed a tissueengineered EPC extracellular-matrix simulating scaffold as an EPC delivery system thatenhanced cell retention and survival. Elements of our work have been upscaled into apreclinical sheep model and also translated into a recently initiated human clinical trial at ourinstitution. In this revised renewal application we propose to study in further depth the specificinteractive mechanisms underlying SDF-mediated EPC neovasculogenesis, develop novel,cytokine and cell delivery platforms, and advance a potential therapeutic sustained releasecytokine strategy in our preclinical sheep model.
Specific Aim 1 will focus on elucidatingmechanistic insights via a novel cardiac-specific SDF conditional knockout mouse, eGFPmarrow reconstitution and EPC tracking, and optical fluorescence quantification of cellular levelperfusion and biomechanical alterations.
Specific Aim 2 will develop an innovative sustainedrelease cytokine hydrogel composite and a unique smooth muscle cell-EPC bilevel cell sheet todeliver biologically supported EPCs to the heart.
Specific Aim 3 will transition the hydrogelcytokine therapeutic strategy into a preclinical sheep model in a minimally invasive operativeapproach. We have generated the preliminary scientific components and assembled the teamexpertise to hopefully successfully achieve these goals.
Myocardial ischemic injury; in all of its forms; from massive heart attack to mild chronic heart injury; has become a tremendous world health problem. Current treatments reopen or bypass large blood vessels in the heart but fail to address a fundamental determinant of long-term benefit; the availability of small; microvessels to deliver oxygen and nutrients to the heart muscle---imagine driving in a country with abundant superhighways but no local roads to take you your final destination. We have developed techniques to stimulate the body's natural stem cells to build these microvessels into injured regions of the heart and propose in this application to study in further depth how these cells work; how to increase the cell's efficiency; and how to prepare this treatment for human clinical use.
|Trubelja, Alen; MacArthur, John W; Sarver, Joseph J et al. (2014) Bioengineered stromal cell-derived factor-1? analogue delivered as an angiogenic therapy significantly restores viscoelastic material properties of infarcted cardiac muscle. J Biomech Eng 136:|
|Atluri, Pavan; Miller, Jordan S; Emery, Robert J et al. (2014) Tissue-engineered, hydrogel-based endothelial progenitor cell therapy robustly revascularizes ischemic myocardium and preserves ventricular function. J Thorac Cardiovasc Surg 148:1090-7; discussion 1097-8|
|Cohen, Jeffrey E; Purcell, Brendan P; MacArthur Jr, John W et al. (2014) A bioengineered hydrogel system enables targeted and sustained intramyocardial delivery of neuregulin, activating the cardiomyocyte cell cycle and enhancing ventricular function in a murine model of ischemic cardiomyopathy. Circ Heart Fail 7:619-26|
|Macarthur Jr, John W; Cohen, Jeffrey E; McGarvey, Jeremy R et al. (2014) Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1* analog in a translational ovine myocardial infarction model. Circ Res 114:650-9|
|MacArthur Jr, John W; Purcell, Brendan P; Shudo, Yasuhiro et al. (2013) Sustained release of engineered stromal cell-derived factor 1-* from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation 128:S79-86|
|Shudo, Yasuhiro; Cohen, Jeffrey E; Macarthur, John W et al. (2013) Spatially oriented, temporally sequential smooth muscle cell-endothelial progenitor cell bi-level cell sheet neovascularizes ischemic myocardium. Circulation 128:S59-68|
|MacArthur Jr, John W; Trubelja, Alen; Shudo, Yasuhiro et al. (2013) Mathematically engineered stromal cell-derived factor-1* stem cell cytokine analog enhances mechanical properties of infarcted myocardium. J Thorac Cardiovasc Surg 145:278-84|
|Atluri, Pavan; Trubelja, Alen; Fairman, Alexander S et al. (2013) Normalization of postinfarct biomechanics using a novel tissue-engineered angiogenic construct. Circulation 128:S95-104|
|Hiesinger, William; Brukman, Matthew J; McCormick, Ryan C et al. (2012) Myocardial tissue elastic properties determined by atomic force microscopy after stromal cell-derived factor 1* angiogenic therapy for acute myocardial infarction in a murine model. J Thorac Cardiovasc Surg 143:962-6|
|Hiesinger, William; Vinogradov, Sergei A; Atluri, Pavan et al. (2011) Oxygen-dependent quenching of phosphorescence used to characterize improved myocardial oxygenation resulting from vasculogenic cytokine therapy. J Appl Physiol 110:1460-5|
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