The vascularization of engineered tissues is critical to the ultimate success of tissue engineering as an organ replacement therapy. The formation of new capillary vessels in vivo, or angiogenesis, also is linked to the pathogenesis of numerous diseases including cancer, and is regulated by local cues within the tissue microenvironment. The general goal of this RENEWAL proposal is to understand the mechanism by which local extracellular matrix (ECM) properties regulate capillary endothelial cell proliferation, gene expression, and capillary tube morphogenesis required in angiogenesis. The investigator has found that adhesion to ECM cooperates with growth factors to generate not only biochemical, but also mechanical signals that are important in driving capillary endothelial cell function. Studies from the past grant period demonstrated that ECM stiffness and composition could be used to regulate proliferation, gene expression, and capillary tube formation by modulating contractile tension generated by the actin cytoskeleton. In this proposal, the investigator proposes to further investigate the role of these mechanical and adhesive cues in regulating angiogenic behaviors.
Specific Aim 1 will be to investigate the role of ECM stiffness in regulating angiogenesis.
Specific Aim 2 will be to investigate the role of ECM peptide ligands in regulating angiogenesis.
Specific Aim 3 will be to investigate the role of spatial organization of the ECM in regulating angiogenesis. Together, these studies will define the mechanisms by which local structural and mechanical properties within ECM modulate endothelial cell function and capillary morphogenesis, and establish new strategies to promote angiogenesis in native ischemic tissues as well as in ex-vivo engineered tissues.
The formation of new capillary vessels in vivo, or angiogenesis, is a rate limiting challenge in the development of engineered implants for organ replacement. Angiogenesis is also critical to many disease processes, including tumor growth and the establishment of atherosclerosis. This project is designed to develop a better understanding of how angiogenesis is regulated by local adhesive and mechanical cues, such that we may better design future approaches to control the growth of blood vessels in tissues.
|Blakely, Brandon L; Dumelin, Christoph E; Trappmann, Britta et al. (2014) A DNA-based molecular probe for optically reporting cellular traction forces. Nat Methods 11:1229-32|
|Rodriguez, Natalia M; Desai, Ravi A; Trappmann, Britta et al. (2014) Micropatterned multicolor dynamically adhesive substrates to control cell adhesion and multicellular organization. Langmuir 30:1327-35|
|Galie, Peter A; Nguyen, Duc-Huy T; Choi, Colin K et al. (2014) Fluid shear stress threshold regulates angiogenic sprouting. Proc Natl Acad Sci U S A 111:7968-73|
|Desai, Ravi A; Rodriguez, Natalia M; Chen, Christopher S (2014) "Stamp-off" to micropattern sparse, multicomponent features. Methods Cell Biol 119:3-16|
|Li, Fengqiang; Xu, Ting; Nguyen, Duc-Huy T et al. (2014) Label-free evaluation of angiogenic sprouting in microengineered devices using ultrahigh-resolution optical coherence microscopy. J Biomed Opt 19:16006|
|Bellas, Evangelia; Chen, Christopher S (2014) Forms, forces, and stem cell fate. Curr Opin Cell Biol 31:92-7|
|Trappmann, Britta; Chen, Christopher S (2013) How cells sense extracellular matrix stiffness: a material's perspective. Curr Opin Biotechnol 24:948-53|
|Lin, Grace L; Cohen, Daniel M; Desai, Ravi A et al. (2013) Activation of beta 1 but not beta 3 integrin increases cell traction forces. FEBS Lett 587:763-9|
|Legant, Wesley R; Choi, Colin K; Miller, Jordan S et al. (2013) Multidimensional traction force microscopy reveals out-of-plane rotational moments about focal adhesions. Proc Natl Acad Sci U S A 110:881-6|
|Dumbauld, David W; Lee, Ted T; Singh, Ankur et al. (2013) How vinculin regulates force transmission. Proc Natl Acad Sci U S A 110:9788-93|
Showing the most recent 10 out of 63 publications