Myofibroblasts in Murine Cutaneous Fibrosis Originate From Adiponectin‐Positive Intradermal Progenitors

Abstract

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 β 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.

FIZZ1-Induced Myofibroblast Transdifferentiation from Adipocytes and Its Potential Role in Dermal Fibrosis and Lipoatrophy

“…6,43 This is further supported by the development of subcutaneous lipoatrophy and concomitant accumulation of fibrous connective tissue at the same location in the mice with adipocyte-specific deletion of PPAR-g. 41,42 A recent cell fate-mapping study that used transgenic mice with adiponectin promoter-driven Cre recombinase to specifically label mature adipocytes also found such a novel link between intradermal adipose loss and dermal fibrosis by showing that adiponectin þ intradermal precursors give rise to dermal myofibroblasts. 29 In this study we report a potential role for FIZZ1 in regulating dermal fibrosis in SSc by targeting the dermal adipocyte and/or its progenitor cell, a suggestion that is supported by in vivo observations of up-regulation of FIZZ2 expression in SSc. 14 …”

“…Therefore, FIZZ1 could cause dedifferentiation of adipocytes followed by differentiation into myofibroblasts in vitro, consistent with a role in adipocyte transdifferentiation to the myofibroblast, a key cell in pathogenesis of chronic fibrosis. 4,29 However, because FIZZ1 caused incomplete (<60%) inhibition of adipocyte gene marker expression, direct adipocyte-to-myofibroblast transdifferentiation without going through a dedifferentiated state cannot be ruled out.…”

PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity

“…An important question for the future is how these stresses alter the expression of PDGF ligands or PDGFRα signaling in a manner that would cause progenitors to transition into profibrotic cells. Intriguingly, a recent study suggested that profibrotic cells in the skin can transition from adiponectin-expressing cells or mature adipocytes in the context of bleomycin-induced fibrosis (Marangoni et al 2015). Although mature adipocytes do not express PDGFRα under normal conditions, its reexpression in disease states could be important.…”

Heterogeneity of adipose tissue in development and metabolic function

“…Dermal adipocytes form a stand-alone depot, distinct from SAT ( Fig. 1) (Driskell et al, 2014;Festa et al, 2011), with potential functions in hair follicle cycling, wound healing and bacterial infection (Alexander et al, 2015;Festa et al, 2011;Marangoni et al, 2015;Zhang et al, 2015). Further studies are needed to elucidate the metabolic role of dermal adipose tissue.…”