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Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive
intradermal progenitors
#MMPMID25504959
Marangoni RG
; Korman BD
; Wei J
; Wood TA
; Graham LV
; Whitfield ML
; Scherer PE
; Tourtellotte WG
; Varga J
Arthritis Rheumatol
2015[Apr]; 67
(4
): 1062-73
PMID25504959
show ga
OBJECTIVE: Accumulation of myofibroblasts in fibrotic skin is a hallmark of
systemic sclerosis (SSc; scleroderma), but the origins of these cells remain
unknown. Because loss of intradermal adipose tissue is a consistent feature of
cutaneous fibrosis, we sought to examine the hypothesis that myofibroblasts
populating fibrotic dermis derive from adipocytic progenitors. METHODS: We
performed genetic fate mapping studies to investigate the loss of intradermal
adipose tissue and its potential role in fibrosis in mice with bleomycin-induced
scleroderma. Modulation of adipocytic phenotypes ex vivo was investigated in
adipose tissue-derived cells in culture. RESULTS: A striking loss of intradermal
adipose tissue and its replacement with fibrous tissue were consistently observed
in mice with bleomycin-induced fibrosis. Loss of adipose tissue and a decline in
the expression of canonical adipogenic markers in lesional skin preceded the
onset of dermal fibrosis and expression of fibrogenic markers. Ex vivo,
subcutaneous adipocytes were driven by transforming growth factor ? to
preferentially undergo fibrogenic differentiation. Cell fate mapping studies in
mice with the adiponectin promoter-driven Cre recombinase transgenic construct
indicated that adiponectin-positive progenitors that are normally confined to the
intradermal adipose tissue compartment were distributed throughout the lesional
dermis over time, lost their adipocytic markers, and expressed myofibroblast
markers in bleomycin-treated mice. CONCLUSION: These observations establish a
novel link between intradermal adipose tissue loss and dermal fibrosis and
demonstrate that adiponectin-positive intradermal progenitors give rise to dermal
myofibroblasts. Adipose tissue loss and adipocyte-myofibroblast transition might
be primary events in the pathogenesis of cutaneous fibrosis that represent novel
potential targets for therapeutic intervention.
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