Tuesday July 03, 2018 from 09:45 to 11:15
Jesus M. Sierra Parraga, Netherlands has been granted the TTS-NTV International Transplantation Science Mentee-Mentor Award
Monocytic Cells Phagocytose Therapeutic Mesenchymal Stem Cells, which Induces Polarization, Relocation and Immune Regulation
Samantha F.H. de Witte1, Franka Luk1, Jesus M. Sierra Parraga1, Madhu Gargesha2, Ana Merino1, Sander S. Korevaar1, Anusha S. Shankar1, Lisa O’Flynn3, Steve J. Elliman3, Debashish Roy2, Michiel G.H. Betjes1, Philip N. Newsome4,5,6, Carla C. Baan1, Martin J. Hoogduijn1.
1Nephrology and Transplantation, Internal Medicine, Erasmus MC, Rotterdam, Netherlands; 2BioInVision Inc., Mayfield Village, OH, United States; 3Orbsen Therapeutics Ltd., Galway, Ireland; 4National Institute for Health Research Liver Biomedical Research Unit , University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, United Kingdom; 5Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; 6Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
Mesenchymal stem or stromal cells (MSC) are under investigation as a potential immunotherapy. MSC are usually administered via intravenous infusion, after which they are trapped in the lungs and die and disappear within a day. The fate of MSC after their disappearance from the lungs is unknown and it is unclear how MSC realize their immunomodulatory effects in their short lifespan.
We examined immunological mechanisms determining the fate of infused MSC and the immunomodulatory response associated with it. Tracking viable and dead human umbilical cord MSC (ucMSC) in mice using Qtracker beads (contained in viable cells) and Hoechst33342 (staining all cells) revealed that viable ucMSC were present in the lungs immediately after infusion. Twenty-four hours later, the majority of ucMSC were dead and found in the lungs and liver where they were contained in monocytic cells of predominantly non-classical Ly6Clow phenotype. Monocytes containing ucMSC were also detected systemically. In vitro experiments confirmed that human CD14++/CD16- classical monocytes polarized towards a non-classical CD14++CD16+CD206+ phenotype after phagocytosis of ucMSC and expressed programmed death ligand-1 and IL-10, while TNF-a was reduced. ucMSC-primed monocytes induced Foxp3+ regulatory T cell formation in mixed lymphocyte reactions.
These results demonstrate that infused MSC are rapidly phagocytosed by monocytes, which subsequently migrate from the lungs to other body sites. Phagocytosis of ucMSC induces phenotypical and functional changes in monocytes, which subsequently modulate cells of the adaptive immune system.
It can be concluded that monocytes play a crucial role in mediating, distributing and transferring the immunomodulatory effect of MSC.
European Union’s Seventh Framework Programme for Research, technological development and demonstration under grant agreement no. 602363..