Cells feel subtle but constant pushes and tugs from their neighbors inside living organisms. Surprisingly, these tiny mechanical cues have a profound effect on how stem cells grow, divide, and turn into the many different cells that make up the human body. Based on recent findings in developmental, cancer, and stem cell biology, we hypothesize that proteins known as cadherins, which allow cells to adhere to one another, are critical to the ability of stem cells to sense and respond to mechanical force. We will use a new form of microscopy to directly visualize the mechanical forces experienced by cadherins in living cells. This information will allow us to determine how stem cells detect force, and how they convert mechanical inputs into changes in gene expression that drive growth and differentiation.
Our work addresses two major, unsolved issues in stem cell biology: the factors that allow stem cells to turn into any kind of cell in the body, and the mechanism by which mechanical cues guide this process. This research will advance biology and medicine by teaching us more about how cells talk to each other using mechanical force, a topic about which very little is known. This project will have a potentially transformative impact on regenerative medicine by providing fundamental knowledge that will be directly applicable to new stem cell treatments, for example for heart disease, and for engineering new tissues to repair or replace diseased tissues or even entire organs.
Cells feel subtle but constant pushes and tugs from their neighbors inside living organisms. Surprisingly, these tiny mechanical cues have a profound effect on how stem cells grow, divide, and turn into the many different cells that make up the human body. However, at present we know almost nothing about how the input provided by mechanical force is connected to changes in stem cell behavior. Our research aims to fill this fundamental gap in our knowledge of how stem cells work. Understanding this aspect of their basic biology will be critical in developing new stem-cell-based treatments for heart disease, and for engineering new tissues to repair or replace diseased tissues and organs.
The goal of this proposal is to explore novel mechanisms by which cadherin complexes interact with mechanical cues to control stem cell behaviors. Cadherins are proteins that enable cells to adhere to one another, and the applicant hypothesizes that cadherin-based mechanisms are essential to the mechanobiology of pluripotent stem cells. Through state-of the-art imaging and molecular biology approaches, the applicant will elucidate the molecular mechanisms by which cadherin complexes maintain pluripotency in human embryonic stem cells (hESCs) (Aim 1). Then, the applicant will use an in vitro model to study the physical forces intrinsic to a three dimensional environment that direct hESC self-renewal and proliferation (Aim 2).
Significance and Innovation
- The proposal addresses an important and understudied area of biology and is likely to break new ground in the broader field of stem cell science.
- The proposed approaches are highly innovative and make use of a number of unique tools developed by the applicant.
- The scientific risk of the application is well balanced by the potential for important new insights that can be gained from the proposed studies.
Feasibility and Experimental Design
- A comprehensive and impressive body of preliminary data supports the experimental rationale and the technical capabilities of the applicant team.
- Novel methodologies and sophisticated assay systems have already been established for conducting the proposed studies.
- The research plan incorporates an attractive combination of technology and basic science.
- While most reviewers considered the experimental design to be appropriately hypothesis-driven, some found the proposed studies to be overly descriptive and suggested that experiments to alter or perturb the mechanical microenvironment should have been included.
Principal Investigator (PI) and Research Team
- The PI has a strong track record of success and a range of high quality publications and was considered a strength of this application.
- A strong team of collaborators provides appropriate expertise and has committed adequate effort to this study.
Responsiveness to the RFA
- This application is responsive to the RFA as it focuses on how mechanotransduction governs hESC self-renewal and differentiation.