Liver mesenchymal stem cells are superior inhibitors of NK cell functions through differences in their secretome compared to other mesenchymal stem cells

Abstract

Liver-resident mesenchymal stem cells (L-MSCs) are superior inhibitors of alloreactive T cell responses compared to their counterparts from bone marrow (BM-MSCs) or adipose tissue (A-MSCs), suggesting a role in liver’s overall tolerogenic microenvironment. Whether L-MSCs also impact NK cell functions differently than other MSCs is not known. We generated and characterized L-MSCs, A-MSCs and BM-MSCs from human tissues. The mass spectrometry analysis demonstrated that L-MSC secretome is uniquely different than that of A-MSC/BM-MSC, with enriched protein sets involved in IFNγ responses and signaling. When co-cultured with primary human NK cells, L-MSCs but not other MSCs, decreased surface expression of activating receptors NKp44 and NKG2D. L-MSCs also decreased IFNγ secretion by IL-2-stimulated NK cells more effectively than other MSCs. Cytolytic function of NK cells were reduced significantly when co-cultured with L-MSCs, whereas A-MSCs or BM-MSCs did not have a major impact. Mechanistic studies showed that the L-MSC-mediated reduction in NK cell cytotoxicity is not through changes in secretion of the cytotoxic proteins Perforin, Granzyme A or B, but through increased production of HLA-C1 found in L-MSC secretome that inhibits NK cells by stimulating their inhibitory receptor KIRDL2/3. L-MSCs are more potent inhibitors of NK cell functions than A-MSC or BM-MSC. Combined with their T cell inhibitory features, these results suggest L-MSCs contribute to the tolerogenic liver microenvironment and liver-induced systemic tolerance often observed after liver transplantation.

Mesenchymal stem cells under epigenetic control – the role of epigenetic machinery in fate decision and functional properties

“…MSCs acquire immunosuppressive functions in a proinflammatory microenvironment (in response to cytokine stimulation such as IL-1α/β, IFNγ, TNF, and IL-17) [ 137 , 138 ], hypoxia conditions [ 139 ], or in response to pharmacological drugs (bortezomib, dexamethasone) [ 140 , 141 ] and chemical/biological agents (LL-37, LPS, curcumin, α-synuclein) [ 142 – 145 ], including epigenetic modifiers (HDAC/DNMT inhibitors) [ 146 , 147 ]. To date, several MSCs mediated immunomodulatory mechanisms have been described, including (1) reduction of T cell-mediated responses by induction of T cell apoptosis, inhibition of T cell proliferation, and supporting of regulatory T cell differentiation [ 148 ]; (2) limitation of B cell responses by regulation B cell proliferation and differentiation towards plasma cells [ 149 ]; (3) inhibition of the cytotoxic function of natural killer (NK) cells [ 150 ]; (4) induction of dendritic cells (DCs) [ 151 ] and monocyte/macrophage (Mo/Ma) tolerogenic properties [ 152 ]; and (5) limitation of inflammatory mediator secretion (Fig. 5 ) [ 153 ].…”

Stromal cells in the tumor microenvironment: accomplices of tumor progression?

“…MSCs can also enhance tumor vascularization by upregulating VEGF and IL-6 [ 155 ], and promote the progression and metastasis of cancer by secreting CCL5, CCL7, and TGF-β [ 142 , 156 ]. Not only that MSCs also affect anti-tumor immune function, such as inhibiting the antitumor activity of NK and DC cells [ 157 ], inducing macrophage M2 polarization [ 158 ], promoting Tregs production, and reducing B cell activation [ 159 ]. In addition, exosomes derived from MSCs can also participate in immunomodulation by regulating immune cell function and altering the secretion of inflammatory factors (such as TNF-α and IL-1β) [ 160 ].…”

Inhibition of LPS-Induced Inflammatory Response of Oral Mesenchymal Stem Cells in the Presence of Galectin-3

“…It also raises the point of the behavior of MSCs in settings of inflammatory processes, which is one of the points addressed by our study. In a series of studies, MSCs have been found to alter antigen-presentation by dendritic cells, affect cytokine production in monocytes/macrophages and CD4+ T helper cells, as well as CD8+ T lymphocytes and natural killer cells cytotoxicity, and control myeloid-derived suppressor cells and Tregs generation and expansion [ 2 , 12 , 21 , 22 , 23 ].…”