Abstract
Human mesenchymal stem/stromal cells (hMSCs) are a promising therapy for acute respiratory distress syndrome (ARDS) and other inflammatory conditions. While considerable research has focused on paracrine effects and mitochondrial transfer that improve lung fluid balance, hMSCs are well known to have immunomodulatory properties as well. Some of these immunomodulatory properties have been related to previously reported paracrine effectors such as indoleamine-2,3-dioxygenase (IDO), but these effects cannot fully account for cell-contact dependent immunomodulation. Here, we report that CD40 is upregulated on hMSCs under the same conditions previously reported to induce IDO. Further, CD40 transcription is also upregulated on hMSCs by ARDS pulmonary edema fluid but not by hydrostatic pulmonary edema fluid. Transcription of CD40, as well as paracrine effectors TSG6 and PTGS2 remained significantly upregulated for at least 12 hours after withdrawal of cytokine stimulation. Finally, induction of this immune phenotype altered the transdifferentiation of hMSCs, one of their hallmark properties. CD40 may play an important role in the immunomodulatory effects of hMSCs in ARDS and inflammation.
Highlights
Prior microarray results indicated that the Human mesenchymal stem/stromal cells (hMSCs) differentiated into a dendritic cell-like phenotype with CD40, CD83, CD68, and MHC class II expression when exposed to CytoMix, but these studies were done with a single biologic replicate [13, 18]
A combination of inflammatory cytokines in the clinically relevant condition acute respiratory distress syndrome (ARDS) leads to upregulation of CD40 gene transcription and cell surface expression on bone marrow-derived mesenchymal stem/stromal cells
Expression of CD40 provides hMSCs with a new pathway to interact with other immune cells
Summary
Mesenchymal stem/stromal cells hMSCs were obtained from Dr D.J. Prockop at the Institute for Regenerative Medicine in Texas A&M Health Science Center (IRM), Dr Shibani Pati at the Blood Systems Research Institute (BSRI), and Dr David McKenna at the University of Minnesota (UM). Cells were cultured as previously described [14]. For these experiments, hMSCs were plated at 1.6 x 105 cells/cm on 60mm untreated tissue culture plates in DMEM-F12 supplemented with antibiotics. TNF-α, IL-1β, and IFN-γ were obtained from R&D Systems. CytoMix consisted of 50 ng/mL TNF-α, IFN-γ, and IL-1β [12]. TNF-α, IFN-γ, and IL-1β were used at 50 ng/mL in various combinations. The hMSCs were exposed to the experimental condition for 24 hours prior to harvesting, unless otherwise noted
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