Abnormal scarring and its accompanying cosmetic, functional and psychological burden is
a major challenge in modern medicine. Pathological scars such as hypertrophic scars or
keloids present cutaneous conditions characterized by excessive collagen deposition which
can be itchy and painful, causing serious functional and aesthetical disabilities. The crucial
role of myofibroblasts and transforming growth factor-beta (TGF-β) signaling in the
pathogenesis of fibrosis and, thus, scarring, is widely accepted. Nevertheless, effective
preventive or therapeutic strategies are still not available despite extensive research.
Autologous fat grafting is a novel approach leading to partly significant improvements of
scar tissue regarding functionality and appearance. Here, fat is harvested from body
deposits and re-injected into areas with scarred tissue. Since adipose tissue does not only
contain adipocytes but is a source for adipose-derived stem cells (ASCs) and even more
cell types, various origins for the observed scar regeneration are conceivable. Regenerative
effects from adipocytes or ASCs are discussed, however, the underlying mechanism is still
unknown. Aiming to unravel the regenerative potential of adipose tissue, paracrine effects
of ASCs and adipocytes on in vitro differentiated myofibroblasts and fibroblasts from
hypertrophic scars were investigated. Interestingly, following incubation with adipocyteconditioned medium, the expression of the myofibroblast marker α-smooth muscle actin
and the extracellular matrix components collagen 1 and 3 decreased significantly indicating
a myofibroblast reprogramming. Secretome analysis, ELISA, Western blot and high
throughput protein analysis indicate a pivotal role of BMP-4 secreted by adipocytes in the
cellular reprogramming. In addition, direct as well as indirect activation of peroxisome
proliferator-activated receptor (PPAR)γ signaling was shown after application of conditioned
medium from adipocytes. Remarkably, speculations about a reciprocal, antagonistic
relationship between PPARɣ and TGF-β do exist which might indicate anti-fibrotic effects
on the part of PPARɣ. Although a myofibroblast-to-adipocyte transition was hypothesised,
myofibroblasts trans-differentiation, however, was not observed.
Overall, adipocytes induce myofibroblast reprogramming via BMP-4 secretion and by direct
as well as indirect activation of PPARγ signaling. These findings highlight the regenerative
potential of adipocytes on scar tissue and may pave the way for novel therapeutic strategies
in the prevention or treatment of hypertrophic scars
