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Cell Transplant. 2018 Jan;27(1):55-69. doi: 10.1177/0963689717723016.

Restoring In Vivo-Like Membrane Lipidomics Promotes Exosome Trophic Behavior from Human Placental Mesenchymal Stromal/Stem Cells.

Author information

1 GUNA - ATTRE (Advanced Therapies and Tissue Regeneration), Innovation Accelerator at CNR, Via Gobetti 101, 40129 Bologna, Italy.
2 National Institute of Biostructures and Biosystems (NIBB), Rome, Italy.
3 Ettore Sansavini Health Science Foundation ONLUS-Lab SWITH, Lugo, Italy.
4 Department of Experimental, Diagnostic and Specialty Medicine, Unit of Nephrology, Dialysis and Renal Transplant, St. Orsola-Malpighi University Hospital, Bologna, Italy.
6 Department of Experimental, Diagnostic and Specialty Medicine, Laboratory of Experimental Cardiology, St. Orsola-Malpighi University Hospital, Bologna, Italy.
5 Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy.
7 Remembrane Srl, Imola, Italy.
8 Division of Obstetrics and Prenatal Medicine, Department of Medical and Surgical Sciences, St. Orsola-Malpighi University Hospital, Bologna, Italy.
9 CNR, Institute of Organic Synthesis and Photoreactivity (Istituto per la Sintesi Organica e la Fotoreattività ISOF), Via Gobetti 101, 40129 Bologna, Italy.


Human mesenchymal stem cells (hMSCs) are an effective tool in regenerative medicine notably for their intrinsic plentiful paracrine activity rather than differentiating properties. The hMSC secretome includes a wide spectrum of regulatory and trophic factors, encompassing several naked molecules as well as different kinds of extracellular vesicles (EVs). Among EVs, exosomes represent an intriguing population, able to shuttle proteins, transcription factors, and genetic materials, with a relevant role in cell-to-cell communication, modulating biological responses in recipient cells. In this context, the extracellular milieu can greatly impact the paracrine activity of stem cells, modifying their metabolism, and the dynamics of vesicle secretion. In the present study, we investigated the effects elicited on exosome patterning by tailored, ad hoc formulated lipid supplementation (Refeed®) in MSCs derived from human fetal membranes (hFM-MSCs). Wound healing experiments revealed that stem cell exposure to exosomes obtained from Refeed®-supplemented hFM-MSCs increased their migratory capability, although the amount of exosomes released after Refeed® supplementation was lower than that yielded from non-supplemented cells. We found that such a decrease was mainly due to a different rate of exosomal exocytosis rather than to an effect of the lipid supplement on the endocytic pathway. Endoplasmic reticulum homeostasis was modified by supplementation, through the upregulation of PKR-like ER kinase (PERK) and inositol-requiring enzyme 1α (IRE1α). Increased expression of these proteins did not lead to stress-induced, unfolded protein response (UPR)-mediated apoptosis, nor did it affect phosphorylation of p38 kinase, suggesting that PERK and IRE1α overexpression was due to augmented metabolic activities mediated by optimization of a cellular feeding network afforded through lipid supplementation. In summary, these results demonstrate how tailored lipid supplementation can successfully modify the paracrine features in hFM-MSCs, impacting both intracellular vesicle trafficking and secreted exosome number and function.


endoplasmic reticulum; exosomes; lipid supplementation; membrane lipidomics; mesenchymal stromal cells

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