Abstract
While thymus is a key organ of the immune system responsible for differentiation and selection of immune T-cells, our understanding of the role of the complex thymic microenvironment in various steps of T-cell development remains elusive. The main objective of this project is to develop microfluidic model of the thymus to investigate biophysical cellular interactions critical for T-cell development. A microfluidic platform capable of culturing multiple cell types in 3D environment will be designed and fabricated. Human thymocytes will then be integrated into the developed system to test survival, proliferation, and migration of developing thymocytes in a thymus-mimicking microenvironment. Taking advantage of this microfluidic based assay T-cell development in a native thymic microenvironment will be studied by incorporating other primary cells of the human thymus and applying cytokine, functional gene and protein expression assays.
References
[1] P. Bonfanti, S. Claudinot, A.W. Amici, A. Farley, C.C. Blackburn, Y. Barrandon. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature, 2010, 466.
[2] Y. Takahama. Journey through the thymus: stromal guides for T-cell development and selection. Nature Reviews Immunology, 2006, 6(2): 127-35.
[3] A. Malandrino, R.D. Kamm, E. Moeendarbary. In vitro modelling of mechanics in cancer metastasis. ACS Biomaterials Science & Engineering, 2017. doi: 10.1021/acsbiomaterials.7b00041.
[4] F. Jessica, D. Conway. “Microfluidic device platform for T cell fate analysis (TECH2P. 907)”, The Journal of immunology, 2015, 206-17.
[5] C.S. Seet, C. He, M.T. Bethune, et al. Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids. Nature Methods, 2017, 1;14(5):521-30.
[6] Y. Shin, S. Han, J.S. Jeon, K. Yamamoto, I.K. Zervantonakis, R. Sudo, R.D. Kamm, S. Chung. Microfluidic assay for simultaneous culture of multiple cell types on surfaces or within hydrogels. Nature protocols, 2012, 7(7):1247.
[7] M.C. Poznansky, I.T. Olszak, R. Foxall, R.H. Evans, A.D. Luster, D.T. Scadden. Active movement of T cells away from a chemokine. Nature medicine, 2000, 1;6(5):543.
[8] H.T. Petrie. Cell migration and the control of postnatal T-cell lymphopoiesis in the thymus. Nature Rev. Immunology, 2003 3:859-66.