Regenerative potential of adipocytes in hypertrophic scars is mediated by myofibroblast reprogramming
Abnormal scarring is a major challenge in modern medicine. The central role of myofibroblasts and TGF-β signaling in scarring is widely accepted, but effective treatment options are missing. Autologous fat grafting is a novel approach that has led to significant improvements in the functionality and appearance of scar tissue. While the underlying mechanism is unknown, the potential role of paracrine effects of adipocytes has been discussed. Hence, with the aim of unraveling the regenerative potential of adipocytes, their effects on in vitro differentiated myofibroblasts and on fibroblasts from hypertrophic scars were investigated. Exposure to adipocyte-conditioned medium significantly decreased the expression of the myofibroblast marker α-SMA and ECM components, indicating the occurrence of myofibroblast reprogramming. Further analysis demonstrated that myofibroblast reprogramming was triggered by BMP-4 and activation of PPARγ signaling initiating tissue remodeling. These findings may pave the way for novel therapeutic strategies for the prevention or treatment of hypertrophic scars.
Adipocytes induce distinct regenerative effects in hypertrophic scar tissue.
Adipocytes secrete several proteins which are involved in wound healing and regeneration.
Adipocytes secrete BMP-4 which activates myofibroblast reprogramming.
Mediators secreted by adipocytes directly and indirectly activate PPARγ which exerts distinct anti-fibrotic effects.
These findings may pave the way for novel therapeutic strategies for the prevention or treatment of hypertrophic scars.
KeywordsMyofibroblast Wound healing Hypertrophic scar Adipocyte Bone morphogenetic protein
The authors thank Patrick Graff and Maria Thon for technical assistance. Moreover, the authors would like to acknowledge the support of Anja Briese and Dr. Christoph Sachse (NMI TT Pharmaservices).
K.H., G.E., and O.K. performed experiments. S.H., L.v.B. (at VUmc), and S.G. (at VUmc) supervised the work. K.H. and S.H. designed the experiments, analyzed the data, and wrote the manuscript. All the authors provided critical review of the manuscript.
This work was financially supported by the Einstein Center for Regenerative Therapies (ECRTs) and the Berlin-Brandenburg School for Regenerative Therapies (BSRT).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 17.Becker M, Maring JA, Schneider M, Herrera Martin AX, Seifert M, Klein O, Braun T, Falk V, Stamm C (2018) Towards a novel patch material for cardiac applications: tissue-specific extracellular matrix introduces essential key features to decellularized amniotic membrane. Int J Mol Sci 19(4):1032CrossRefGoogle Scholar
- 19.Zvonic S, Lefevre M, Kilroy G, Floyd ZE, DeLany JP, Kheterpal I, Gravois A, Dow R, White A, Wu X et al (2007) Secretome of primary cultures of human adipose-derived stem cells: modulation of serpins by adipogenesis. Mol Cell Proteomics 6(1):18–28Google Scholar
- 28.Spiekman M, Przybyt E, Plantinga JA, Gibbs S, van der Lei B, Harmsen MC (2014) Adipose tissue-derived stromal cells inhibit TGF-beta1-induced differentiation of human dermal fibroblasts and keloid scar-derived fibroblasts in a paracrine fashion. Plast Reconstr Surg 134(4):699–712CrossRefGoogle Scholar
- 31.Burgess HA, Daugherty LE, Thatcher TH, Lakatos HF, Ray DM, Redonnet M, Phipps RP, Sime PJ (2005) PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol 288(6):L1146–L1153CrossRefGoogle Scholar
- 33.Wei J, Ghosh AK, Sargent JL, Komura K, Wu M, Huang QQ, Jain M, Whitfield ML, Feghali-Bostwick C, Varga J (2010) PPARgamma downregulation by TGFss in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis. PLoS One 5(11):e13778CrossRefGoogle Scholar
- 44.Wertheimer T, Velardi E, Tsai J, Cooper K, Xiao S, Kloss CC, Ottmuller KJ, Mokhtari Z, Brede C, deRoos P et al (2018) Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration. Sci Immunol 3(19); doi: 10.1126/sciimmunol.aal2736Google Scholar