Human Adipose-Derived Stem Cells Impair Natural Killer Cell Function and Exhibit Low Susceptibility to Natural Killer-Mediated Lysis

Abstract

Human adipose-derived stem cells (hASCs) have been successfully used in treating numerous diseases. However, several aspects need to be considered, particularly in the context of allogeneic cell therapy. To better understand hASCs-host interactions, we studied the phenotype of hASCs and their modulatory effect on natural killer (NK) cells by using bone marrow-mesenchymal stem cells (hBM-MSCs) as a reference. The hASCs displayed a lower susceptibility to NK cell-mediated lysis and a lower expression of ligands for DNAM-1 when compared with hBM-MSCs. Moreover, here we demonstrated that hASCs and hBM-MSCs can modulate NK cells through the action of soluble factors such as indoleamine 2,3-dioxygenase. Altogether, these results suggest that for an adoptive cell therapy based on the transfer of allogeneic hASCs, the NK-hASCs crosstalk will not result in an immediate recognition of the transferred cells. Thus, hASCs may remain in the tissue long enough to balance the immune response before being cleared.

Mesenchymal stem cells as a therapeutic tool to treat sepsis

“…MSCs are considered a promising tool for cell therapy, in particular for inflammatory diseases, based on their immunomodulatory properties and paracrine effects through trophic factors with anti-fibrotic, anti-apoptotic or pro-angiogenic properties [29,30] . MSCs regulate the function of a broad range of immune cells [30][31][32][33][34][35][36][37] , and are activated by inflammatory mediators released from activated immune cells (i.e., IFNγ, IL1β and TNFα) [38,39] . The mechanisms involved in the immunoregulatory activity of MSCs are still under investigation but rely on both cell contact-dependent mechanisms (i.e., Jagged1-Notch1 interaction, Fas-Fas-L interaction) [40,41] and paracrine effects through the release of soluble factors including hepatocyte growth factor, prostaglandin-E2 (PGE2), TGF-β1, nitric oxide (NO), IL-10, IL-6, heme oxygenase-1 (HO-1), HLA-G5 or the enzymatic activity of indoleamine 2,3-dioxygenase [42] .…”

The promising role for adipose-derived mesenchymal stem cells in tissue regeneration

“…MSCs have been known to suppress activity of NK cells with regards to IFN-γ secretion and proliferation [51,71,72]. ASCs, specifically, are capable of such suppression [73] and are themselves poorly susceptible to lysis by NK cells [74].…”

Human Adipose-Derived Stromal/Stem Cells Induce Functional CD4+CD25+FoxP3+CD127−Regulatory T Cells Under Low Oxygen Culture Conditions

“…ASC activation or suppression of one or more specific Tcell subsets may significantly affect the observed overall growth inhibition or stimulation of T cells [5][6][7]9,[12][13][14][15][16][17]. Several studies have demonstrated that ASCs inhibit cells of both the innate and adaptive immune response through secretion of soluble factors such as prostaglandin E 2 , TGF-b1, hepatocyte growth factor, and production of factors that include inducible nitric oxide synthase and indoleamine 2,3-dioxygenase [7,9,12,13,[20][21][22].…”

“…Several studies have demonstrated that ASCs inhibit cells of both the innate and adaptive immune response through secretion of soluble factors such as prostaglandin E 2 , TGF-b1, hepatocyte growth factor, and production of factors that include inducible nitric oxide synthase and indoleamine 2,3-dioxygenase [7,9,12,13,[20][21][22]. Another potential mechanism of immune interference involves ASC-mediated induction of iT regs from naive CD4 + T cells by direct contact.…”

“…Under ambient (21%) O 2 conditions in vitro, ASCs inhibited proliferation of alloactivated peripheral blood mononuclear cells (PBMCs) and CD4 + T cells, and stimulated proliferation of resting CD4 + T cells [7,8]. T-cell proliferation continued after extended culture in the absence of ASCs [6,7,9].…”