Regenerative potential of adipocytes in hypertrophic scars is mediated by myofibroblast reprogramming

Abstract

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.

Key messages

  • 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.

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Acknowledgments

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).

Funding

This work was financially supported by the Einstein Center for Regenerative Therapies (ECRTs) and the Berlin-Brandenburg School for Regenerative Therapies (BSRT).

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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.

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Correspondence to Sarah Hedtrich.

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Hoerst, K., van den Broek, L., Sachse, C. et al. Regenerative potential of adipocytes in hypertrophic scars is mediated by myofibroblast reprogramming. J Mol Med 97, 761–775 (2019). https://doi.org/10.1007/s00109-019-01772-2

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Keywords

  • Myofibroblast
  • Wound healing
  • Hypertrophic scar
  • Adipocyte
  • Bone morphogenetic protein