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.
|Steele, Amanda N; Cai, Lei; Truong, Vi N et al. (2017) A novel protein-engineered hepatocyte growth factor analog released via a shear-thinning injectable hydrogel enhances post-infarction ventricular function. Biotechnol Bioeng 114:2379-2389|
|Kawamura, Masashi; Paulsen, Michael J; Goldstone, Andrew B et al. (2017) Tissue-engineered smooth muscle cell and endothelial progenitor cell bi-level cell sheets prevent progression of cardiac dysfunction, microvascular dysfunction, and interstitial fibrosis in a rodent model of type 1 diabetes-induced cardiomyopathy. Cardiovasc Diabetol 16:142|
|Edwards, Bryan B; Fairman, Alexander S; Cohen, Jeffrey E et al. (2016) Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb. J Vasc Surg 64:1093-9|
|Hou, Luqia; Kim, Joseph J; Woo, Y Joseph et al. (2016) Stem cell-based therapies to promote angiogenesis in ischemic cardiovascular disease. Am J Physiol Heart Circ Physiol 310:H455-65|
|Shudo, Yasuhiro; Cohen, Jeffrey E; Goldstone, Andrew B et al. (2016) Isolation and trans-differentiation of mesenchymal stromal cells into smooth muscle cells: Utility and applicability for cell-sheet engineering. Cytotherapy 18:510-7|
|Shudo, Yasuhiro; Cohen, Jeffrey E; MacArthur, John W et al. (2015) A Tissue-Engineered Chondrocyte Cell Sheet Induces Extracellular Matrix Modification to Enhance Ventricular Biomechanics and Attenuate Myocardial Stiffness in Ischemic Cardiomyopathy. Tissue Eng Part A 21:2515-25|
|Rodell, Christopher B; MacArthur, John W; Dorsey, Shauna M et al. (2015) Shear-Thinning Supramolecular Hydrogels with Secondary Autonomous Covalent Crosslinking to Modulate Viscoelastic Properties In Vivo. Adv Funct Mater 25:636-644|
|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|
|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|
Showing the most recent 10 out of 24 publications