title: Inactivated Mesenchymal Stem Cells Maintain Immunomodulatory Capacity.
abstract: Mesenchymal stem cells (MSC) are studied as a cell therapeutic agent for treatment of various immune diseases. However, therapy with living culture-expanded cells comes with safety concerns. Furthermore, development of effective MSC immunotherapy is hampered by lack of knowledge of the mechanisms of action and the therapeutic components of MSC. Such knowledge allows better identification of diseases that are responsive to MSC treatment, optimization of the MSC product, and development of therapy based on functional components of MSC. To close in on the components that carry the therapeutic immunomodulatory activity of MSC, we generated MSC that were unable to respond to inflammatory signals or secrete immunomodulatory factors, but preserved their cellular integrity [heat-inactivated MSC (HI-MSC)]. Secretome-deficient HI-MSC and control MSC showed the same biodistribution and persistence after infusion in mice with ischemic kidney injury. Both control and HI-MSC induced mild inflammatory responses in healthy mice and dramatic increases in interleukin-10, and reductions in interferon gamma levels in sepsis mice. In vitro experiments showed that opposite to control MSC, HI-MSC lacked the capability to suppress T-cell proliferation or induce regulatory B-cell formation. However, both HI-MSC and control MSC modulated monocyte function in response to lipopolysaccharides. The results of this study demonstrate that, in particular disease models, the immunomodulatory effect of MSC does not depend on their secretome or active cross-talk with immune cells, but on recognition of MSC by monocytic cells. These findings provide a new view on MSC-induced immunomodulation and help identify key components of the therapeutic effects of MSC.
authors.affiliation: 1 Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Franka
authors.initials: F
authors.lastname: Luk
authors.affiliation: 1 Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Samantha F H
authors.initials: SF
authors.lastname: de Witte
authors.affiliation: 1 Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Sander S
authors.initials: SS
authors.lastname: Korevaar
authors.affiliation: 2 Department of Internal Medicine, University Medical Center Groningen , Groningen, the Netherlands .
authors.forename: Marieke
authors.initials: M
authors.lastname: Roemeling-van Rhijn
authors.affiliation: 1 Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Marcella
authors.initials: M
authors.lastname: Franquesa
authors.affiliation: 1 Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Tanja
authors.initials: T
authors.lastname: Strini
authors.affiliation: 3 Transplant Surgery, Department of Surgery, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Sandra
authors.initials: S
authors.lastname: van den Engel
authors.affiliation: 4 BioInVision, Inc. , Mayfield Village, Ohio.
authors.forename: Madhusudhana
authors.initials: M
authors.lastname: Gargesha
authors.affiliation: 4 BioInVision, Inc. , Mayfield Village, Ohio.
authors.forename: Debashish
authors.initials: D
authors.lastname: Roy
authors.affiliation: 3 Transplant Surgery, Department of Surgery, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Frank J M F
authors.initials: FJ
authors.lastname: Dor
authors.affiliation: 5 The Research Institute and Division of Hematology/Oncology/BMT, Nationwide Children's Hospital , Columbus, Ohio.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Horwitz
authors.affiliation: 3 Transplant Surgery, Department of Surgery, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Ron W F
authors.initials: RW
authors.lastname: de Bruin
authors.affiliation: 1 Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Michiel G H
authors.initials: MG
authors.lastname: Betjes
authors.affiliation: 1 Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
authors.affiliation: 1 Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC-University Medical Center , Rotterdam, the Netherlands .
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hoogduijn
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D056747:Immunomodulation; D016130:Immunophenotyping; D007249:Inflammation / Q000473:pathology; D007262:Infusions, Intravenous; D008070:Lipopolysaccharides; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D018805:Sepsis / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology; D014018:Tissue Distribution
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides