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Mechanochemical Actuators of Embryonic Epithelial Contractility

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Mechanochemical Actuators of Embryonic Epithelial Contractility Mechanochemical actuators of embryonic epithelial contractility YongTae Kima,1, Melis Hazara, Deepthi S. Vijayraghavanb, Jiho Songa, Timothy R. Jacksonb, Sagar D. Joshib,2, William C. Messnerc,3,4, Lance A. Davidsond,4, and Philip R. LeDuce,4 aDepartment of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213; bDepartment of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260; cDepartments of Mechanical Engineering and Electrical and Computer Engineering and Robotics Institute, Carnegie Mellon University, Pittsburgh, PA 15213; dDepartments of Bioengineering, Developmental Biology, and Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260; and eDepartments of Mechanical Engineering, Biomedical Engineering, Computational Biology, and Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213 Edited by Shu Chien, University of California, San Diego, La Jolla, CA, and approved August 18, 2014 (received for review March 20, 2014) Spatiotemporal regulation of cell contractility coordinates cell shape embryonic epithelium to the same degree as cell lysate (16). Ex- change to construct tissue architecture and ultimately directs the tracellular ATP has been shown to activate contraction in a range of morphology and function of the organism. Here we show that cell types from endothelial cells of the cardiovascular system to contractility responses to spatially and temporally controlled chem- skeletal muscle cells (17). Cells exposed to a stream of ATP for 10 s ical stimuli depend much more strongly on intercellular mechanical contract and subsequently relax over 3 min. Using this stimulation connections than on biochemical cues in both stimulated tissues and protocol, we identified a level of stimulation (50-μMATP)that adjacent cells. We investigate how the cell contractility is triggered consistently triggered contraction (Fig. S1) and produced distinct within an embryonic epithelial sheet by local ligand stimulation and patterns of local strain in the tissue (Fig. 1 C–E; for details on strain coordinates a long-range contraction response. Our custom micro- maps see Materials and Methods). The threshold level of ATP fluidic control system allows spatiotemporally controlled stimulation concentration does not depend on the stimulation duration as long with extracellular ATP, which results in locally distinct contractility as it is not longer than 20 s, which is a limitation due to the delay followed by mechanical strain pattern formation. The stimulation– between ATP exposure and the contraction response. The con- response circuit exposed here provides a better understanding of ENGINEERING traction response after 20 s causes initially adjacent cells to be how morphogenetic processes integrate responses to stimulation and how intercellular responses are transmitted across multiple drawn into the stream and exposed to ATP, which complicates cells. These findings may enable one to create a biological actuator interpretations of the results due to additional cells being stimu- that actively drives morphogenesis. lated. We note that the stream delivered to the tissue was strictly laminar with sharp concentration gradients across the stream microfluidics | multicellular | mechanotransduction | signaling Significance BIOLOGY hysiological control systems have evolved diverse strategies to DEVELOPMENTAL Psense the environment, transduce signals, and actuate contrac- This study shows how cell contractility is triggered within an tile responses. One such strategy involves the actuation of non- embryonic epithelial sheet by local ligand stimulation and coor- muscle cell contractility to drive a wide range of developmental dinates a long-range contraction response. The stimulation– processes as well as normal physiological and pathological disease response circuit exposed here provides a better understanding of states (1–5). The contractile behaviors of cells and their inter- how morphogenetic processes integrate responses to stimulation actions in multicellular arrays are not only critical in shaping and and how intercellular responses are transmitted across multiple guiding tissue formation (e.g., epithelial folding) for the suc- cells. Understanding the systems-level behavior of biological sig- cessful outcome of development programs (6, 7), but also play naling networks may allow us to control biological actuators with a major role in the pathology of tumor growth, the invasion- engineered spatiotemporal stimulation. Our findings will provide metastasis cascade, wound healing, and tissue regeneration (8, 9). a better understanding of contractility-dependent morphogenetic From a signaling standpoint, embryonic development is a dy- movements as well as the intercellular communication pathways namic process where cells interact and coordinate force genera- critical during developmental biology, synthetic morphogenesis, tion as their identities are patterned by spatiotemporally applied and multicellular mechanotransduction signaling. chemical stimuli. There has been considerable debate over the effectiveness of intra- versus intercellular signaling during de- Author contributions: Y.K., W.C.M., L.A.D., and P.R.L. designed research; Y.K., M.H., D.S.V., – and J.S. performed research; Y.K., M.H., D.S.V., J.S., T.R.J., S.D.J., W.C.M., L.A.D., and P.R.L. velopment (10, 11); nevertheless, the cell cell signaling and the contributed new reagents/analytic tools; Y.K., M.H., D.S.V., J.S., T.R.J., W.C.M., L.A.D., and coordination of a variety of multicellular responses are known to P.R.L. analyzed data; S.D.J. and L.A.D. identified the use of extracellular ATP for inducing be mediated by gap-junction-dependent intercellular communi- contractility in Xenopus embryonic tissues; and Y.K., W.C.M., L.A.D., and P.R.L. wrote cation (12, 13). However, recent findings from studies of cell the paper. mechanics indicate that mechanical cues can be as potent as The authors declare no conflict of interest. chemical factors in directing cell differentiation and behaviors This article is a PNAS Direct Submission. and suggest a role in modulating signal transduction pathways 1Present address: The George W. Woodruff School of Mechanical Engineering, Wallace H. (14, 15). Less clear is whether signal transduction can be modu- Coulter Department of Biomedical Engineering, Institute for Electronics and Nanotech- lated by mechanical connections during morphogenesis. nology, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332. Results and Discussion 2Present address: American Air Liquide Inc., Delaware Research and Technology Center, Newark, DE 19702. To investigate the complex integrated response of a multicellular 3Present address: Department of Mechanical Engineering, Tufts University, Medford, system and investigate the mechanochemical response and actua- MA 02155. tion, we cultured an intact epithelial sheet adhered to a fibronectin 4To whom correspondence may be addressed. Email: [email protected], william.messner@ extracellular matrix substrate within a custom microfluidic chamber tufts.edu, or [email protected]. – and exposed a narrow band of 4 5 cells within the sheet to ATP This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (Fig. 1 A and B). ATP can trigger contraction in the Xenopus 1073/pnas.1405209111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1405209111 PNAS Early Edition | 1of6 Downloaded by guest on October 2, 2021 Fig. 1. Understanding mechanochemical actuation through epithelial contractility in an X. laevis embryonic tissue. (A) Schematic and confocal image (front view) showing microfluidic stream of extracellular ATP applied to a Xenopus embryonic tissue. This stream profile was spatiotemporally controlled through our feedback microfluidic control of the inlet pressure at the streams (for the performance of our microfluidic control system see Movie S1)(40–42). Pho- tograph of the microfluidic device, in which a single AC tissue explant is being locally stimulated by the central stream bounded by culture media (DFA). Computation fluid dynamics simulation predicting flow patterns around a tissue model (Movie S2). The cells exposed to a stream of extracellular ATP contract whereas the neighboring cells stretch. (B) Microscope image of a Xenopus embryonic tissue with a gray stream indicating the location of ATP (for the contractility of the tissue see Movie S3). (Scale bar: 100 μm.) (C–E) Strain map responses of locally ATP stimulated Xenopus tissue indicating mechanical actuation at (C) 20-, (D) 60-, and (E) 100 s after 10-s ATP stimulation. The color maps overlay the corresponding microscope images of the tissue in the microfluidic channel and indicate the strain distribution in the tissue. (F) Strains at the middle section of the tissue perpendicular to the stream. The data for the black solid line correspond to the image in C, the red dashed line to D, and the blue dashed-dotted line to E. The gray rectangular area represents the location of the ATP stream that covers the tissue. (G–I) Strain map responses of locally ATP stimulated tissue modeled with FE analysis. G, H, and I attempt to simulate C, D, and E, respectively. (J and K) Time-lapse images showing multiple cells of embryonic epithelial sheet in a tissue explant with ATP stream (J)and the strains of the cells (K) on the tissue (Movie S4). A pulse ATP stream was applied at 0 s and lasted for 45 s. (Scale bar: 50 μm.) Strains
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