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 Ly6C phenotype. Monocytes containing ucMSC were also detected systemically. In vitro experiments confirmed that human CD14 /CD16 classical monocytes polarized toward a non-classical CD14 CD16 CD206 phenotype after phagocytosis of ucMSC and expressed programmed death ligand-1 and IL-10, while TNF-α 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. Stem Cells 2018;36:602-615.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

No abstract

The worldwide increase in the number of patients with end-stage renal disease leads to a growing waiting list for kidney transplantation resulting from the scarcity of kidney donors. Therefore, alternative treatment options for patients with end-stage renal disease are being sought. In vitro differentiation of stem cells into renal tissue is a promising approach to repair nonfunctional kidney tissue. Impressive headway has been made in the use of stem cells with the use of adult renal progenitor cells, embryonic stem cells, and induced pluripotent stem cells for the development toward primitive kidney structures. Currently, efforts are directed at improving long-term maintenance and stability of the cells. This review aims to provide a comprehensive overview of the cell sources used for the generation of kidney cells and strategies used for transplantation in in vivo models. Furthermore, it provides a perspective on stability and safety during future clinical application of in vitro generated kidney cells.