Fibrosis is a central component of numerous major diseases and is implicated in an estimated 45% of all deaths in the developed world. Hallmarks of fibrosis include myofibroblast (MF) induction, excessive MF proliferation and matrix synthesis, and stiffening or contraction of the extracellular matrix (ECM), but how these changes are interrelated and feedback to reinforce the fibrotic process is not understood. This is in part because we lack a fundamental understanding of how cells sense, mechanically respond to, and in turn alter the structure and mechanics of their surroundings during fibrosis. To fill this gap in our knowledge and develop treatments that target the mechanisms of fibrosis, we need experimental approaches that allow us to 1) accurately capture the fibrous structure and mechanical behavior of tissues, and 2) monitor the mechanical forces that drive MF differentiation, proliferation, and subsequent fibrotic stiffening. The overall focus of the proposed work is to connect intracellular and extracellular mechanics during the initiation and reinforcement of MF induction and proliferation. We will measure MF contractile forces in a newly established synthetic ECM that is fibrous, mechanically tunable, and can be reorganized by cells. Using this platform, we will examine whether TGF- induces RhoA-mediated fibril reorganization to increase traction force generation and subsequent MF induction and proliferation. With an understanding of how MF induction and proliferation is initiated, we will proceed to examine how increased MF cell density reinforces fibrotic changes during the R00 phase. We will determine whether tension within the fibrillar ECM generated by high densities of contractile MFs spurs further MF induction. Next, we will examine the effect of high MF density on fibrillar network stiffening via ECM synthesis, and query whether this in turn also promotes MF induction. This work will shine light on biophysical mechanisms common to fibrotic changes accompanying numerous diseases, and may provide a test bed for therapeutics that can disrupt this process.

Public Health Relevance

During fibrosis, abnormal myofibroblasts impair organ function by stiffening tissues, but how tissue stiffening causes healthy cells to become myofibroblasts is not understood. The proposed work will measure cellular forces in a synthetic fibrous tissue model to study the underlying mechanics of myofibroblast transformation, with the long term goal of establishing a test bed for therapeutics that target this process to stop fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL124322-04
Application #
9405912
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lundberg, Martha
Project Start
2017-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Engineering (All Types)
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Trappmann, Britta; Baker, Brendon M; Polacheck, William J et al. (2017) Matrix degradability controls multicellularity of 3D cell migration. Nat Commun 8:371
Cao, Xuan; Ban, Ehsan; Baker, Brendon M et al. (2017) Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices. Proc Natl Acad Sci U S A 114:E4549-E4555
Baker, Brendon M; Trappmann, Britta; Wang, William Y et al. (2015) Cell-mediated fibre recruitment drives extracellular matrix mechanosensing inĀ engineered fibrillar microenvironments. Nat Mater 14:1262-8