Myocardial ischemia, infarction, and heart failure constitute a disease spectrum which is rapidly becoming one of the foremost global health challenges. Current therapies focus upon pharmacologic optimization and macrorevascularization via PCI and CABG. Reconstructive and replacement therapies are limited in applicability or availability. A significant unmet need is that of microrevascularizatio. Repeated studies have demonstrated survival advantage in patients with robust collateralization. Thus the presence of endogenous revascularization and repair mechanisms exist and the benefits are clear;but the native potency is generally inadequate. In the initial funding period, we studied the primary effectors of endogenous microrevascularization, endothelial progenitor stem cells (EPC) and their potent chemokine stromal cell derived factor 1-alpha (SDF). We were able to significantly augment microvascular angiogenesis and improve local tissue biomechanical properties, ventricular geometry and cardiac function after myocardial ischemic injury. Via computational protein engineering, we then designed and synthesized a supra-efficient SDF analog as well as initiated a project to embed EPCs in a vitronectin-based extracellular-matrix simulating scaffold to enhance cell retention and survival. Elements of this work have been upscaled into a preclinical sheep model and also translated into a recently initiated human clinical trial at our institution. In this renewal application we propose to study in further depth the specific interactive mechanisms underlying SDF-mediated EPC neovasculogenesis, develop novel, clinically translatable delivery platforms that enhance EPC function and survival, and refine these in our preclinical sheep model in preparation for potential human clinical investigation.
Specific Aim 1 will focus on elucidating mechanistic insights via eGFP marrow reconstitution and tracking, a novel myocardial-specific SDF conditional knockout mouse, and optical fluorescence quantification of cellular level perfusion, oxygenation and energetics.
Specific Aim 2 will develop innovative cellular composites based upon biologic extracellular matrix, cell sheet technology and synthetic 3-dimensional printed microscaffolds.
Specific Aim 3 will transition this therapeutic strategy into a preclinical sheep model in minimally invasive operative and catheter- based approaches. We have generated the preliminary scientific components and assembled the team expertise to hopefully successfully achieve these goals.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL089315-07
Application #
8853534
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Adhikari, Bishow B
Project Start
2007-07-01
Project End
2019-06-30
Budget Start
2014-08-15
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
$379,465
Indirect Cost
$129,465
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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

Showing the most recent 10 out of 16 publications