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Dynamics of cell-extracellular matrix interactions during fibrosis

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Human fibrotic lung tissue, stained for myofibroblasts, endothelial cells, and matrix (Image credit: Jingyi Xia).

Fibrosis is a central component of numerous diseases, including liver cirrhosis, idiopathic pulmonary fibrosis, post-infarct cardiac scarring, and cancer; as such, it is implicated in an estimated 45% of all deaths in the developed world.  These diverse pathologies similarly progress toward organ failure through myofibroblast-mediated overproduction of an excessively stiff ECM.  These myofibroblasts are the very same cells that are critical to wound healing and regeneration.  What differentiates wound healing from fibrosis? What feedback signals from the microenvironment diverts a healing response toward fibrosis? Answering these questions requires a fundamental understanding of how cells sense and mechanically respond to their extracellular environs, and how this response mediates changes in ECM structure and mechanics that feedback to further propagate fibrosis.  We develop approaches that allow us to study the evolving structure and mechanical properties of fibrous ECM, while monitoring the cellular forces that drive myofibroblast signaling.  This work will shine light on biophysical mechanisms common to fibrotic changes accompanying numerous diseases, and could lead to therapies that promote regenerative healing over fibrotic scar formation.

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We use synthetic biomaterials to build 3D models of fibrotic interstitial tissues.

Trainees:  Jingyi Xia
Collaborators:  Bethany Moore, Matthew Kutys, Claudia Loebel, Vincent Fiore
Relevant publications:
The Role of Rho GTPases During Fibroblast Spreading, Migration, and Myofibroblast Differentiation in 3D Synthetic Fibrous Matrices
Matera DL, Lee AT, Hiraki HL, Baker BM.
Cellular and Molecular Bioengineering. 2021 Sep 2;14(5):381-396. PMID: 34777599; PMCID: PMC8548490.
New directions and dimensions for bioengineered models of fibrosis
Matera DL, Wang WY, Baker BM.
Nature Reviews Materials, 2021, 6: 192-195.
Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in myofibroblast differentiation
Matera DL, DiLillo KM, Smith MR, Davidson CD, Parikh R, Said M, Wilke CA, Lombaert IM, Arnold KB, Moore BB, Baker BM.
Science Advances, 2020, 10.1126/sciadv.abb5069.
Myofibroblast activation in synthetic fibrous matrices composed of dextran vinyl sulfone
Davidson CD, Jayco DKP, Matera DL, DePalma SJ, Hiraki HL, Wang WY, Baker BM.
Acta Biomaterialia, 2020, 105: 78-86. 
Fiber density modulates cell spreading in 3D interstitial matrix mimetics
Matera DL, Wang WY, Smith MR, Shikanov A, Baker BM.
ACS Biomaterials Science & Engineering, 2019. 10.1021/acsbiomaterials.9b00141

Engineered fibrous networks to investigate the influence of fiber mechanics on myofibroblast differentiation
Davidson MD, Song KH, Lee MH, Llewellyn J, Du Y, Baker BM, Wells RG, Burdick JA.
ACS Biomaterials Science & Engineering, 2019.  10.1021/acsbiomaterials.8b01276

Therapeutic targeting of TAZ and YAP by dimethyl fumarate in systemic sclerosis fibrosis
Toyama T, Looney AP, Baker BM, Stawski L, Haines P, Simms R, Szymaniak AD, Varelas X, Trojanowska M.
Journal of Investigative Dermatology, 2018, 138(1):78-88. 

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