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Polacheck, William J.

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Polacheck

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William J.

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Polacheck, William J.
Author's Publications: search.filters.isAuthorOfPublication.8879b5c9-e053-4931-8f55-8895ed595d3f

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    Matrix degradability controls multicellularity of 3D cell migration
    (Nature Publishing Group UK, 2017) Trappmann, Britta; Baker, Brendon M.; Polacheck, William J.; Choi, Colin K.; Burdick, Jason A.; Chen, Christopher
    A major challenge in tissue engineering is the development of materials that can support angiogenesis, wherein endothelial cells from existing vasculature invade the surrounding matrix to form new vascular structures. To identify material properties that impact angiogenesis, here we have developed an in vitro model whereby molded tubular channels inside a synthetic hydrogel are seeded with endothelial cells and subjected to chemokine gradients within a microfluidic device. To accomplish precision molding of hydrogels and successful integration with microfluidics, we developed a class of hydrogels that could be macromolded and micromolded with high shape and size fidelity by eliminating swelling after polymerization. Using this material, we demonstrate that matrix degradability switches three-dimensional endothelial cell invasion between two distinct modes: single-cell migration and the multicellular, strand-like invasion required for angiogenesis. The ability to incorporate these tunable hydrogels into geometrically constrained settings will enable a wide range of previously inaccessible biomedical applications.
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    A non-canonical Notch complex regulates adherens junctions and vascular barrier function
    (2017) Polacheck, William J.; Kutys, Matthew; Yang, Jinling; Eyckmans, Jeroen; Wu, Yinyu; Vasavada, Hema; Hirschi, Karen K.; Chen, Christopher
    The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and hemostasis1. Hemodynamic shear stress plays a critical role in maintaining endothelial barrier function2, but how this occurs remains unknown. Here, using an engineered organotypic model of perfused microvessels and confirming in mouse models, we identify that activation of the Notch1 transmembrane receptor directly regulates vascular barrier function through a non-canonical, transcription independent signaling mechanism that drives adherens junction assembly. Shear stress triggers Dll4-dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain – the key domain that mediates barrier establishment. Expression of the Notch1 transmembrane domain is sufficient to rescue Notch1 knockout-induced defects in barrier function, and does so by catalyzing the formation of a novel receptor complex in the plasma membrane consisting of VE-cadherin, the transmembrane protein tyrosine phosphatase LAR, and the Rac1 GEF Trio. This complex activates Rac1 to drive adherens junction assembly and establish barrier function. Canonical Notch transcriptional signaling is highly conserved throughout metazoans and is required for many processes in vascular development, including arterial-venous differentiation3, angiogenesis4, and remodeling5; here, we establish the existence of a previously unappreciated non-canonical cortical signaling pathway for Notch1 that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodeling.
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    Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy
    (American Association for the Advancement of Science (AAAS), 2015) Hinson, John Travis; Chopra, Anant; Nafissi, N.; Polacheck, William J.; Benson, Craig Carlyle; Swist, S.; Gorham, Joshua; Yang, Luhan; Schafer, S.; Sheng, Calvin Chen; Haghighi, Alireza; Homsy, Jason; Hubner, N.; Church, George; Cook, S. A.; Linke, Wolfgang; Chen, Christopher; Seidman, Jonathan; Seidman, Christine
    Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell–derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.