Collaborative Research: EAGER: The Role of Cell-Cell Forces in the Cadherin Switch Model

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The research objective of this EArly-Concept Grant for Exploratory Research (EAGER) is to establish the link between the changing cadherin expression, or the cadherin switch model, and the evolving mechanical microenvironment that differentiating mesenchymal stem cells (MSCs) encounter during bone formation. MSCs experience both cell-matrix, or integrin-mediated, and cell-cell, or cadherin-mediated, forces during differentiation. However, the role of cell-cell forces through cadherins has been largely neglected despite that cadherin regulation is essential to normal bone formation. The "cadherin switch" specifies that as MSCs differentiate in to bone forming cells, one cadherin is up regulated and another is down regulated. The switch parallels the changing mechanical environment during bone formation: MSCs begin in soft marrow (~1kPa) and differentiate into bone matrix-producing cells in stiff, unmineralized matrix (10s of kPa). This work aims to relate the cadherin switch to the changing mechanical microenvironment for MSCs. The approach uses a combination of two tools: Electrohydrodynamic (E-Jet) and 3D, full-field traction force microscopy (3D TFM). E-Jet will pattern both proteins and stiffness on polyacrylamide substrates and enable manipulation cell-cell and cell-substrate forces. 3D TFM will measure the forces thus quantitatively establishing the relationship. The influence of cell-cell forces in differentiation and bone formation has largely been neglected. Results from this work could lead to new treatments for bone diseases and a more complete understanding of tissue development both for bone and for other tissues. Through the work the relatively new techniques, 3D TFM and E-Jet patterning of cell culture substrates, will be made more accessible to a broader scientific community. The educational component focuses on graduate student training and research experiences through interactions between institutions and across disciplines. The research will also be used to highlight the breadth of the field of Mechanical Engineering (ME) specifically for the Campus Middle School (CMS) for Girls, with the goal of making ME more accessible to these and other K-12 students who otherwise may not be interested in ME based on preconceptions of the field.