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J Tissue Eng Regen Med. 2017 Jan 19. doi: 10.1002/term.2417. [Epub ahead of print]

Unbiased and quantitative proteomics reveals highly increased angiogenesis induction by the secretome of mesenchymal stromal cells isolated from fetal rather than adult skin.

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  • 1Fondazione Ri.MED, Palermo, Italy.
  • 2Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), Palermo, Italy.


Scarless wound healing and functional regeneration are typical processes of the fetus, gradually lost during post-natal life, and maximally attributed to fetal skin tissue and induced by fetal skin fibroblasts. The latter have been successfully applied to post-natal wounds, with clear advantages compared with autologous dermis grafts or adult fibroblast applications. Our goal was to functionally identify and uncover key factors and mechanisms through the analysis of secretomes, the principal players in all cell therapies based on mesenchymal stromal cells (MSCs). Cell secretomes also putatively mediate skin regenerative effects achieved in clinical applications of fetal skin fibroblasts. An innovative and unbiased approach of comparative and quantitative proteomics of cell conditioned media enabled us to gain knowledge of key molecules and processes from a translational perspective. Using banks of fetal and adult skin fibroblasts that we previously characterized as being MSCs, we discovered secretome changes by identification and comparative quantification, distinguishing secretome signatures of fetal skin MSCs putatively relevant for therapeutic microenvironment modulation. The uncovered proteins can trigger, directly and by modulation of extracellular matrix, angiogenesis, thus highlighting its key role towards scarless wound healing. The angiogenic trigger was functionally validated and corroborated in vitro, with fetal skin MSC secretomes stabilizing and inducing the formation of capillary-like networks by endothelial cells and fetal liver MSCs, respectively. Both our approach and results may aid in the development of cell-based and cell-free products for skin regeneration in acute or chronic injury, and also for wound healing in the regeneration of other tissues.


angiogenesis; fetal skin MSCs; liquid chromatography tandem mass spectrometry; microenvironment modulation; quantitative proteomics; secretome; stable isotope labeling by amino acids in cell culture; tissue regeneration

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