Biomedical Engineering Reference
In-Depth Information
Table 11.14.
in myofibroblast differentiation (Source: [
1474
]; Abl:
Abelson protein Tyr kinase; MAPK: mitogen-activated protein kinase; PAK: P21-activated kinase;
PI3K, phosphatidylinositol 3-kinase; rSMAD: receptor-regulated SMAD; TOR: target of ra-
pamycin). Homodimer TGF
Signaling
from
TGF
β
R2 complex that auto- and transphosphorylates.
It targets myocardin during myofibroblast differentiation. Alternative TGF
β
1 binds to T
β
R1-T
β
1 pathway triggers the
release of matrix metallopeptidases MMP2, MMP9, and MMP13, as well as plasminogen activator,
thereby matrix disruption.
β
Pathway
Effect
TGF
β
-T
β
R1/2-rSMAD-SMAD4
Matrix production;
myofibroblast
differentiation
TGF
β
-T
β
R1/2-PI3K-PKB-TOR; PI3K-PAK2-Abl1
Fibroblast proliferation
RhoA/Ras/MAP3K7-ERK1/2/JNK/P38MAPK
Matrix remodeling
Non-canonical ALK1-SMAD1/5/8
Matrix degradation
stellate cells (e.g., hepatic Ito and pancreatic stellate cells); (6) stromal progenitor
cells; and (7) circulating mesenchymal stem and precursor cells.
Three features discriminate myofibroblasts from fibroblasts [
1474
]: (1) bundles
of contractile microfilaments; (2) abundant cell-matrix attachment sites; and (3) in-
tercellular adherens and gap junctions.
Myofibroblasts produce and remodel the extracellular matrix. They produce al-
ternatively spliced fibronectin isoform with extradomain A (EDA [fibronectin
EDA
]).
In addition to fibronectin
EDA
, they synthesize collagen-1 and -3. They can generate
matrix tension. Moreover, they secrete angiogenic and pro-inflammatory factors.
Differentiation of myofibroblasts occurs during wound healing. Numerous agents
trigger myofibroblast differentiation, especially transforming growth factor-
β
(Ta-
ble
11.14
)[
1474
]. Fibronectin
EDA
cooperates with TGF-
β
to activate
α
-actin-2 and
form
-actin-2-based stress fibers, whereas protomyofibroblasts contain stress fibers
composed of only
α
-actins.
Myofibroblast recruitment and altered TGF
β
-and
γ
1 signaling are involved in the early
stage of thoracic aortic aneurysms [
1474
]. Production of TGF
β
1 in myofibroblasts
followed by secretion and autocrine control upregulates the expression of the
focal adhesion molecule TGF
β
1I1
68
β
1-induced transcript TGF
β
that reduces the
proliferation of pathogenic myofibroblasts [
1474
].
Transforming growth factor-
1 effect depends on its concentration. At low
concentration, it stimulates proliferation and migration of fibroblasts and smooth
myocytes. At high concentration, it precludes cell proliferation. Local TGF
β
β
1
overexpression can stabilize abdominal aortic aneurysms [
1474
].
Angiotensin-2 can prime myofibroblast differentiation via nicotinamide ade-
nine dinucleotide phosphate oxidase that generates reactive oxygen species and
activation of P38MAPK and JNK [
1474
]. In addition, angiotensin-2 enhances
68
A.k.a. 55-kDa androgen receptor-associated protein ARA55 and hydrogen peroxide-inducible
clone-5 protein HIC5.
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