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Identifying Mechanisms of Homeostatic Signaling in Fibroblast Differentiation

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Abstract

Fibroblasts play an important role in the wound-healing process by generating extracellular matrix (ECM) and undergoing differentiation into myofibroblasts, but these cells can also be involved in pathologic remodeling of tissue. Nascent ECM provides a substrate for re-epithelialization to occur, restoring damaged tissue to a functional state. Dysregulation of this process can result in fibrosis—stiffening and scarring of the tissue. Current treatments cannot halt or reverse this process. The molecular mechanisms underlying fibrotic dysregulation are poorly understood, providing an untapped pool of potential therapeutic targets. Transforming growth factor-\(\upbeta \) (\(\hbox {TGF-}\upbeta )\) and adhesion signaling are involved in inducing fibroblast differentiation into \(\upalpha \)-smooth muscle actin (\(\upalpha \hbox {SMA}\)) expressing myofibroblasts, while prostaglandin \(\hbox {E}_{2}\) (\(\hbox {PGE}_{2})\) has been shown to antagonize \(\hbox {TGF}\upbeta \) signaling; however, the temporal and mechanistic details of this relationship have not yet been fully characterized. We measured \(\upalpha \hbox {SMA}\), a marker of fibroblast to myofibroblast differentiation, as a function of: \(\hbox {TGF-}{\upbeta }1\) receptor–ligand complex internalization, \(\hbox {PGE}_{2}\) binding, and adhesion signaling and developed a mathematical model capturing the molecular mechanisms of fibroblast differentiation. Using our model, we predict the following: Periodic dosing with \(\hbox {PGE}_{2}\) temporarily renders fibroblasts incapable of differentiation and refractory to additional \(\hbox {TGF-}{\upbeta }1\) stimulation; conversely, periodic dosing with \(\hbox {TGF-}{\upbeta }1\) in the presence of \(\hbox {PGE}_{2}\) induces a reduced signal response that can be further inhibited by the addition of more \(\hbox {PGE}_{2}\). Controlled fibroblast differentiation is necessary for effective wound healing; however, excessive accumulation of \(\upalpha \hbox {SMA}\)-expressing myofibroblasts can result in fibrosis. Homeostasis of \(\upalpha \hbox {SMA}\) in our model requires a balance of positive and negative regulatory signals. Sensitivity analysis predicts that \(\hbox {PGE}_{2}\) availability, \(\hbox {TGF-}{\upbeta }1\) availability, and the rate of \(\hbox {TGF-}{\upbeta }1\) receptor recycling each highly influence the rates of \(\upalpha \hbox {SMA}\) production. With this model, we are able to demonstrate that regulation of both \(\hbox {TGF-}{\upbeta }1\) and \(\hbox {PGE}_{2}\) signaling levels is essential for preventing fibroblast dysregulation.

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Acknowledgments

This research was supported by the following Grants: R01 EB012579, R01 HL 110811 (both awarded to D.E.K. and J.J.L.), and R01 HL 115618 (awarded to B.B.M.).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA

    Hayley C. Warsinske, Bethany B. Moore & Denise E. Kirschner

  2. Immunology Graduate Program, University of Michigan, Ann Arbor, MI, USA

    Shanna L. Ashley

  3. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA

    Jennifer J. Linderman

  4. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    Bethany B. Moore

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  1. Hayley C. Warsinske
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  2. Shanna L. Ashley
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  5. Denise E. Kirschner
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Correspondence to Denise E. Kirschner.

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Warsinske, H.C., Ashley, S.L., Linderman, J.J. et al. Identifying Mechanisms of Homeostatic Signaling in Fibroblast Differentiation. Bull Math Biol 77, 1556–1582 (2015). https://doi.org/10.1007/s11538-015-0096-2

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