Journal article
Efferocytosis of viable versus heat-inactivated MSC induces human monocytes to distinct immunosuppressive phenotypes
Stem cell research & therapy, Vol.14(1), 206
08/17/2023
DOI: 10.1186/s13287-023-03443-z
PMCID: PMC10433682
PMID: 37592321
Abstract
Background: Immunomodulation by mesenchymal stromal cells (MSCs) can occur through trophic factor mechanisms, however, intravenously infused MSCs are rapidly cleared from the body yet a potent immunotherapeutic response is still observed. Recent work suggests that monocytes contribute to the clearance of MSCs via efferocytosis, the body's natural mechanism for clearing dead and dying cells in a non-inflammatory manner. This begs the questions of how variations in MSC quality affect monocyte phenotype and if viable MSCs are even needed to elicit an immunosuppressive response.
Methods: Herein, we sought to dissect MSC's trophic mechanism from their efferocytic mechanisms and determine if the viability of MSCs prior to efferocytosis influences the resultant phenotype of monocytes. We cultured viable or heat-inactivated human umbilical cord MSCs with human peripheral blood mononuclear cells for 24 h and observed changes in monocyte surface marker expression and secretion profile. To isolate the effect of efferocytosis from MSC trophic factors, we used cell separation techniques to remove non-efferocytosed MSCs before challenging monocytes to suppress T-cells or respond to inflammatory stimuli. For all experiments, viable and heat-inactivated efferocytic-licensing of monocytes were compared to non-efferocytic-licensing control.
Results: We found that monocytes efferocytose viable and heat-inactivated MSCs equally, but only viable MSC-licensed monocytes suppress activated T-cells and suppression occurred even after depletion of residual MSCs. This provides direct evidence that monocytes that efferocytose viable MSCs are immunosuppressive. Further characterization of monocytes after efferocytosis showed that uptake of viable-but not heat inactivated-MSC resulted in monocytes secreting IL-10 and producing kynurenine. When monocytes were challenged with LPS, IL-2, and IFN-γ to simulate sepsis, monocytes that had efferocytosed viable MSC had higher levels of IDO while monocytes that efferocytosed heat inactivated-MSCs produced the lowest levels of TNF-α.
Conclusion: Collectively, these studies show that the quality of MSCs efferocytosed by monocytes polarize monocytes toward distinctive immunosuppressive phenotypes and highlights the need to tailor MSC therapies for specific indications.
Details
- Title: Subtitle
- Efferocytosis of viable versus heat-inactivated MSC induces human monocytes to distinct immunosuppressive phenotypes
- Creators
- Michael V. Schrodt - University of IowaRiley M. Behan-Bush - University of IowaJesse N. Liszewski - University of IowaMadeleine E. Humpal-Pash - University of IowaLauren K. Boland - University of IowaSabrina M. Scroggins - University of IowaDonna A. Santillan - University of IowaJames A. Ankrum - Iowa Policy Project
- Resource Type
- Journal article
- Publication Details
- Stem cell research & therapy, Vol.14(1), 206
- DOI
- 10.1186/s13287-023-03443-z
- PMID
- 37592321
- PMCID
- PMC10433682
- NLM abbreviation
- Stem Cell Res Ther
- ISSN
- 1757-6512
- eISSN
- 1757-6512
- Publisher
- BioMed Central
- Grant note
- T32 GM139776 / ; P42 ES013661 / ; P30CA086862 / ;
- Language
- English
- Date published
- 08/17/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Iowa Technology Institute; Obstetrics and Gynecology; Fraternal Order of Eagles Diabetes Research Center; Iowa Superfund Research Program
- Record Identifier
- 9984455489102771
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