Identification of the Molecular Mechanism in Scar Regeneration by Studying the Cellular Crosstalk between Adipocytes and Connective Tissue

Abstract

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.