Ischemic heart disease affects over 150 million people worldwide and remains a leading cause of death for mankind. While overall mortality after myocardial infarction has improved, many patients ultimately succumb to heart failure despite pharmacologic, revascularization, and reconstructive therapies due to microvascular perfusion deficits which remain unaddressed. Targeted therapies such as cytokine, stem cell, and tissue- engineering approaches to myocardial revascularization, repair, and regeneration have had varied success, likely due to limitations in mechanistic understanding and suboptimal delivery systems. Thus, novel approaches to microrevascularization are greatly needed. In the recent funding period, we further elucidated the native signaling mechanisms of the angiogenic cytokine stromal cell-derived factor 1? (SDF) with its target, endothelial progenitor stem cells, to better harness its therapeutic effect during post-infarction myocardial repair. Furthermore, we synthesized a supra-efficient engineered SDF analog (ESA) and delivered it via a novel biomaterial for prolonged therapeutic effect. These strategies revealed robust angiogenesis, improved cardiomyocyte survival, preserved myocardial tissue biomechanics, reduced adverse post-injury remodeling, and enhanced cardiac functional recovery. We also designed and constructed a tissue-engineered bilayer cell sheet and demonstrated its ability to improve angiogenesis and ventricular remodeling. Finally, we have translated elements of our work into pre-clinical large animal models to evaluate the potential of these therapies to reach human clinical trials. This renewal application proposes to further define the mechanisms underlying the therapeutic effects of SDF, and to optimize cytokine delivery platforms for large animal and eventual human clinical translation.
Aim 1 seeks to delineate SDF/ESA molecular structure to guide synthesis of novel analogs with enhanced efficacy, genetically manipulate SDF signaling to identify therapeutic targeting opportunities, and study the effects of microrevascularization on cellular perfusion, tissue biomechanics, and ventricular function.
Aim 2 proposes the development of two innovative bioengineered cytokine delivery platforms for treating myocardial ischemia. One encompasses a novel shear-thinning hydrogel with dual cytokine release modalities and the capacity for percutaneous transcatheter delivery. Another involves fabricating a tissue-engineered SDF-eluting vascular conduit to enable simultaneous macro- and microrevascularization.
Aim 3 strives to scale these innovative strategies to large animal pre-clinical models of percutaneous transcatheter therapeutics and minimally invasive coronary artery bypass grafting with synthesized bioconduits. The proposed experiments will yield important knowledge on potential clinical therapies for coronary artery disease, myocardial infarction, and heart failure.

Public Health Relevance

Ischemic heart disease is a leading cause of death in the United States and worldwide, and constitutes a major health crisis. While major coronary vessel blockages can be reopened or bypassed, these treatments do not address the critical loss of small microvessels that deliver the blood, oxygen, and nutrients to the heart muscle cells. Our research aims to study molecular and cellular mechanisms, stimulate endogenous repair pathways, and develop innovative bioengineered systems to regrow these vital vessels inside the heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089315-13
Application #
10124423
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Adhikari, Bishow B
Project Start
2008-03-15
Project End
2024-02-29
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
13
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Goldstone, Andrew B; Burnett, Cassandra E; Cohen, Jeffery E et al. (2018) SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells. J Cardiovasc Transl Res 11:274-284
Ingason, Arnar B; Goldstone, Andrew B; Paulsen, Michael J et al. (2018) Angiogenesis precedes cardiomyocyte migration in regenerating mammalian hearts. J Thorac Cardiovasc Surg 155:1118-1127.e1
von Bornstädt, Daniel; Wang, Hanjay; Paulsen, Michael J et al. (2018) Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold-Stabilized, Tubular Bilevel Cell Sheets. Circulation 138:2130-2144
Shudo, Yasuhiro; Goldstone, Andrew B; Cohen, Jeffrey E et al. (2017) Layered smooth muscle cell-endothelial progenitor cell sheets derived from the bone marrow augment postinfarction ventricular function. J Thorac Cardiovasc Surg 154:955-963
Mirabella, T; MacArthur, J W; Cheng, D et al. (2017) 3D-printed vascular networks direct therapeutic angiogenesis in ischaemia. Nat Biomed Eng 1:
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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
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
Cohen, Jeffrey E; Goldstone, Andrew B; Paulsen, Michael J et al. (2017) An innovative biologic system for photon-powered myocardium in the ischemic heart. Sci Adv 3:e1603078
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

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