My group works at the interface of engineering and biology to understand the links between mechanical forces, biological form, and cell function in health and disease. The intertwining of structural, mechanical, and biochemical processes is inherent to how multicellular organisms organize during development, adapt to physical stresses around them, and devolve during disease. Our goal is to establish a path to investigate, understand, and ultimately control these linked physical-biological processes, to build biomimetic tissues as experimental models, and to direct tissue remodeling and regeneration.
To untangle the many factors that impinge on cell and tissue structure, mechanics, and function, we have pioneered numerous synthetic microenvironments to control the spatial organization, mechanics, composition, or temporal presentation of materials and cells. We combine these tools with molecular cell biological approaches to uncover fundamental mechanisms that regulate cellular adhesions, forces, and function. These insights in turn drive our efforts to build biomimetic 3D culture platforms, control tissue remodeling, and promote regeneration.
At this interface between technology, cell biology, and medicine, our mission is to provide new tools for biomedicine, to gain new insights into the control of cell and tissue function, to train scientific leaders that transcend traditional disciplines, and to demonstrate the boundless opportunities for impacting the future of research, medicine, and education.
Our research program encompasses several overlapping efforts in vascular, cardiac, and stem cell biology and engineering.
Mechanobiology Across Scales
We are investigating the underlying mechanisms driving the interplay between cellular forces, cell-cell and cell-matrix adhesions, and structure-function at the molecular, cellular, and tissue levels in a variety of physiologic and pathologic settings.
186. Baker, B.M., Trappmann, B., Wang, W.Y., Sakar, M.S., Kim, I.L., Shenoy, V.B., Burdick, J.A., Chen, C.S. (2015) Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat. Mater. 14(12):1262-1268. PMCID: PMC4654682
189. Sakar, M.S., Eyckmans, J., Pieters, R., Eberli, D., Nelson, B.J., Chen, C.S. (2016) Cellular forces and matrix assembly coordinate fibrous tissue repair. Nat Comm. 7(11036):1-8. PMCID: PMC4799373207. Trappmann, B., Baker, B.M., Polacheck, W.J., Choi, C.K., Burdick, J.A., Chen, C.S. (2017) Matrix degradability controls multicellularity of 3D cell migration. Nat Commun. 8(1):371. PMCID: PMC5575316
212. Polacheck, W.J., Kutys, M.L., Yang, J., Eyckmans, J., Wu, Y., Vasavada, H., Hirschi, K.K., Chen, C.S. (2017) A non-canonical Notch complex regulates adherens junctions and vascular barrier function. Nature. 552(7684):258-262. PMCID: PMC5730479213. Chopra, A, Kutys, M.L., Zhang, K., Polacheck, W.J., Sheng, C.C., Luu, R.J., Eyckmans, J., Hinson, J.T., Seidman, J.G., Seidman, C.E., Chen, C.S. (2018) Force Generation via β-Cardiac Myosin, Titin, and α-Actinin Drives Cardiac Sarcomere Assembly from Cell-Matrix Adhesions. Dev. Cell. 44(1):87-96. PMCID: PMC6421364
227. Yoon C., Choi C., Stapleton S., Mirabella T., Howes C., Dong L., King J., Yang J., Oberai A., Eyckmans J., Chen C.S. (2019) Myosin IIA-mediated forces regulate multicellular integrity during vascular sprouting. Mol Biol Cell. 16:1974-1984. doi: 10.1091/mbc.E19-02-0076 PMCID: PMC6727772
3D Organotypic Culture Platforms
We are building 3D organotypic culture platforms that mimic human tissues and disease, in order to
1) study the design principles for driving cell and tissue structure and phenotype
2) investigate underlying physiologic and pathologic processes.
Our initial focus has been in modeling cardiac muscle and perfused vasculature, but have extended these insights into a variety of other settings.
185. Hinson, J.T., Chopra, A., Nafissi, N., Polacheck, W.J., Benson, C.C., Swist, S., Gorham, J., Yang, L., Schafer, S., Sheng, C.C., Haghighi, A., Homsy, J., Hubner, N., Church, G., Cook, A.S., Linke, W.A., Chen, C.S. Seidman, J.G., Seidman, C.E. (2015) Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyophathy. Science 349(6251):982-986. PMCID: PMC4618316
206. Alimperti, S., Mirabella, T., Bajaj, V., Polacheck, W., Pirone, D.M., Duffield, J., Eyckmans, J., Assoian, R.K., Chen, C.S. (2017) Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N-cadherin balance in mural cell-endothelial cell-regulated barrier function. Proc. Natl. Acad. Sci. USA 114(33):8758-8763. PMCID: PMC5565405
212. Polacheck, W.J., Kutys, M.L., Yang, J., Eyckmans, J., Wu, Y., Vasavada, H., Hirschi, K.K., Chen, C.S. (2017) A non-canonical Notch complex regulates adherens junctions and vascular barrier function. Nature. 552(7684):258-262. PMCID: PMC5730479
226. Du Y., Khandekar G., Llewellyn J., Polacheck W., Chen C.S., Wells R.G. (2019) A Bile Duct-on-a-Chip with Organ-Level Functions. Hepatology. 71(4), 1350-1363 doi: 10.1002/hep.30918 PMCID: PMC7048662
228. Nguyen D.T., Lee E., Alimperti S., Norgard R.J., Wong A., Lee J.J., Eyckmans J., Stanger B.Z., Chen C.S. (2019) A Biomimetic Pancreatic Cancer On-Chip Reveals Endothelial Ablation via ALK7 Signaling. Sci Adv. 28;5 doi: 10.1126/sciadv.aav6789. PMCID: PMC6713506
235. ML Kutys, WJ Polacheck, MK Welch, KA Gagnon, T Koorman, S Kim, L Li, ...Uncovering mutation-specific morphogenic phenotypes and paracrine-mediated vessel dysfunction in a biomimetic vascularized mammary duct platform Nature communications 11 (1), 1-11 1 2020
Vascularization and Regeneration
We are applying our insights in the regulation of endothelial cells and stem cells in order to establish new therapeutic strategies to engineer vascularization and organ repair for regenerative medicine applications.
205. Stevens, K.R., Scull, M.A., Ramanan, V., Fortin, C.L., Chaturvedi, R.R., Knouse, K.A., Xiao, J.W., Fung, C., Mirabella, T., Chen, A.X., McCue, M.G., Yang, M.T., Fleming, H.E., Chung, K., de Jong, Y.P., Chen, C.S., Rice, C.M., Bhatia, S.N. (2017) In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease. Sci. Transl. Med. 9(399).pii:aah5505. PMCID: PMC5896001
210. Mirabella, T., MacArthur, J.W., Cheng, D., Ozaki, C.K., Woo, Y.J., Yang, M.T., Chen, C.S. (2017) 3D-printed vascular networks direct therapeutic angiogenesis in ischaemia. Nat. Biomed. Eng. 1(83) doi:10.1038/s41551-017-0083. PMCID: PMC5837070
224. Seeherman H.J., Berasi S.P., Brown, C.T., Martinez, R.X., Juo, Z.S., Jelinsky, S., Cain, M.J., Grode, J., Tumelty, K.E., Bohner, M., Grinberg, O., Orr, N., Shoseyov, O., Eyckmans, J., Chen, C.S., Morales, P.R., Wilson, C.G., Vanderploeg, E.J., Wozney, J.M. (2019) A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix. Sci Transl Med. 11 PMID: 31019025
234. HHG Song, A Lammers, S Sundaram, L Rubio, AX Chen, L Li, ... Transient Support from Fibroblasts is Sufficient to Drive Functional Vascularization in Engineered Tissues Advanced Functional Materials, 2003777