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2015 ; 77
(8
): 1556-82
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Identifying Mechanisms of Homeostatic Signaling in Fibroblast Differentiation
#MMPMID26384829
Warsinske HC
; Ashley SL
; Linderman JJ
; Moore BB
; Kirschner DE
Bull Math Biol
2015[Aug]; 77
(8
): 1556-82
PMID26384829
show ga
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-? (TGF-?) and adhesion signaling
are involved in inducing fibroblast differentiation into ?-smooth muscle actin
(?SMA) expressing myofibroblasts, while prostaglandin E? (PGE?) has been shown to
antagonize TGF-? signaling; however, the temporal and mechanistic details of this
relationship have not yet been fully characterized. We measured ?SMA, a marker of
fibroblast to myofibroblast differentiation, as a function of: TGF-?1
receptor-ligand complex internalization, PGE? 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
PGE? temporarily renders fibroblasts incapable of differentiation and refractory
to additional TGF-?1 stimulation; conversely, periodic dosing with TGF-?1 in the
presence of PGE? induces a reduced signal response that can be further inhibited
by the addition of more PGE?. Controlled fibroblast differentiation is necessary
for effective wound healing; however, excessive accumulation of ?SMA-expressing
myofibroblasts can result in fibrosis. Homeostasis of ?SMA in our model requires
a balance of positive and negative regulatory signals. Sensitivity analysis
predicts that PGE? availability, TGF-?1 availability, and the rate of TGF-?1
receptor recycling each highly influence the rates of ?SMA production. With this
model, we are able to demonstrate that regulation of both TGF-?1 and PGE?
signaling levels is essential for preventing fibroblast dysregulation.
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