Over 8 million people in the US suffer from peripheral arterial disease (PAD). A feature of PAD is dysfunction or damage to the vascular endothelium, a layer of endothelial cells (ECs) that exerts control over vascular reactivity, remodeling and angiogenesis. Cell-based approaches to restore or regenerate the endothelium so as to enhance the angiogenic response to ischemia hold promise for the treatment of PAD. A candidate source of ECs is induced pluripotent stem cells (iPSCs), which are derived from reprogrammed somatic cells. The iPSCs maintain unlimited self renewal and the ability to differentiate into cardiovascular lineages, including ECs. In order to utilize iPSCs therapeutically, the cells must first be differentiated into the lineage of interest and then delivered efficiently to the site of ischemic disease. Stem cell phenotype and function are influenced by microenvironmental cues including the extracellular matrix (ECM), a biological scaffolding material that provides structural support and modulates cellular function and phenotype. ECM regulation of cell behavior is mediated by integrin transmembrane receptors that connect the ECM to the intracellular cytoskeleton and activate downstream signaling pathways. ECMs have been shown to enhance the yields of EC lineages of pluripotent stem cells, but whether these ECMs are optimal for EC differentiation is unknown because there has been no systematic study to assess the role of matrix-mediated differentiation. The goal of this project is to define the role of ECMs in the differentiation of iPSCs into ECs, maintenance of EC phenotype, and therapeutic enhancement of angiogenesis in animal models of PAD. This project will utilize a high-throughput ECM microarray platform to optimize the efficiency of matrix-mediated iPSC differentiation into ECs. The mechanistic role of ECM-integrin interactions during EC differentiation and maintenance will also be examined. Finally, iPSC-derived ECs and ECMs will be assessed in animal models of PAD for vascular regeneration. By gaining fundamental insights into mechanisms of ECM-mediated differentiation and angiogenic function, the applicant intends to provide a stronger foundation of knowledge and improved methods for the clinical development and application of iPSC-derived ECs for vascular repair. The applicant seeks to establish a tenure-track academic career in advancing the treatment of vascular diseases using bioengineering and molecular cell biology techniques. The applicant is a postdoctoral fellow in the Stanford University School of Medicine, where she is being trained in stem cell and molecular cellular techniques in the research group of Dr. John Cooke, a well-established investigator in the field of endothelial biology and PAD therapies. Additional guidance in her training and transition to independence will be provided by renowned experts in the fields of stem cell development, matrix biology, tissue engineering, biomaterials, and biostatistics.

Public Health Relevance

The goal of this project is to define the role of extracellular matrices in the differentiation of induced pluripotent stem cells into endothelial cells, maintenance of endothelial phenotype, and therapeutic enhancement of angiogenesis for repair of peripheral arterial disease. This project can result in the development of new treatments to repair vascular diseases, which has far-reaching impact on public health.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Lundberg, Martha
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Palo Alto Institute for Research & Edu, Inc.
Palo Alto
United States
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Giordano, Samantha; Zhao, Xiangmin; Xing, Daisy et al. (2016) Targeted delivery of human iPS-ECs overexpressing IL-8 receptors inhibits neointimal and inflammatory responses to vascular injury in the rat. Am J Physiol Heart Circ Physiol 310:H705-15
Kim, Joseph J; Hou, Luqia; Huang, Ngan F (2016) Vascularization of three-dimensional engineered tissues for regenerative medicine applications. Acta Biomater 41:17-26
Hou, Luqia; Coller, John; Natu, Vanita et al. (2016) Combinatorial extracellular matrix microenvironments promote survival and phenotype of human induced pluripotent stem cell-derived endothelial cells in hypoxia. Acta Biomater 44:188-99
Nakayama, Karina H; Surya, Vinay N; Gole, Monica et al. (2016) Nanoscale Patterning of Extracellular Matrix Alters Endothelial Function under Shear Stress. Nano Lett 16:410-9
Nakayama, Karina H; Joshi, Prajakta A; Lai, Edwina S et al. (2015) Bilayered vascular graft derived from human induced pluripotent stem cells with biomimetic structure and function. Regen Med 10:745-55
Dash, Rajesh; Kim, Paul J; Matsuura, Yuka et al. (2015) Manganese-Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri-Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia-Reperfusion Model. J Am Heart Assoc 4:
Nakayama, Karina H; Hong, Guosong; Lee, Jerry C et al. (2015) Aligned-Braided Nanofibrillar Scaffold with Endothelial Cells Enhances Arteriogenesis. ACS Nano 9:6900-8
Burridge, Paul W; Metzler, Scott A; Nakayama, Karina H et al. (2014) Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes. Am J Transl Res 6:724-35
Mulyasasmita, Widya; Cai, Lei; Dewi, Ruby E et al. (2014) Avidity-controlled hydrogels for injectable co-delivery of induced pluripotent stem cell-derived endothelial cells and growth factors. J Control Release 191:71-81
Ghebremariam, Yohannes T; Huang, Ngan F; Kambhampati, Swetha et al. (2014) Characterization of a fluorescent probe for imaging nitric oxide. J Vasc Res 51:68-79

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