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?-Smooth muscle actin is an inconsistent marker of fibroblasts responsible for
force-dependent TGF? activation or collagen production across multiple models of
organ fibrosis
#MMPMID26944089
Sun KH
; Chang Y
; Reed NI
; Sheppard D
Am J Physiol Lung Cell Mol Physiol
2016[May]; 310
(9
): L824-36
PMID26944089
show ga
Fibrosis is a common pathological sequela of tissue injury or inflammation, and
is a major cause of organ failure. Subsets of fibroblasts contribute to tissue
fibrosis in multiple ways, including generating contractile force to activate
integrin-bound, latent TGF? and secreting excess amounts of collagens and other
extracellular matrix proteins (ECM) that make up pathologic scar. However, the
precise fibroblast subsets that drive fibrosis have been poorly understood. In
the absence of well-characterized markers, ?-smooth muscle actin (?SMA) is often
used to identify pathologic fibroblasts, and some authors have equated ?SMA(+)
cells with contractile myofibroblasts and proposed that these cells are the major
source of ECM. Here, we investigated how well ?SMA expression describes
fibroblast subsets responsible for TGF? activation and collagen production in
three commonly used models of organ fibrosis that we previously reported could be
inhibited by loss of ?v integrins on all fibroblasts (using PDGFR?-Cre).
Interestingly, ?SMA-directed deletion of ?v integrins protected mice from
CCl4-induced hepatic fibrosis, but not bleomycin-induced pulmonary or unilateral
ureteral obstruction-induced renal fibrosis. Using Col-EGFP/?SMA-RFP dual
reporter mice, we found that only a minority of collagen-producing cells
coexpress ?SMA in the fibrotic lung and kidney. Notably, Col-EGFP(+)?SMA-RFP(-)
cells isolated from the fibrotic lung and kidney were equally capable of
activating TGF? as were Col-EGFP(+)?SMA-RFP(+) cells from the same organ, and
this TGF? activation was blocked by a TGF?-blocking antibody and an inhibitor of
nonmuscle myosin, respectively. Taken together, our results suggest that ?SMA is
an inconsistent marker of contractile and collagen-producing fibroblasts in
murine experimental models of organ fibrosis.
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