Abstract
Mesenchymal stem cells (MSCs) are becoming an increasingly popular therapeutic option among patients with a broad range of ailments to modulate immunity and induce regeneration. The majority of patients receiving these MSC therapies are on concurrent medication or have ongoing infection. In the present study, we examined the effect of immunosuppressive drugs and lipopolysaccharides (LPS)/endotoxins on the secretory profile, migration towards site of injury, and suppression of lymphocyte proliferation of bone marrow-derived MSCs (BMSCs). Generally, LPS coculture augmented the secretory capacity of BMSCs while exposure to immunosuppressive drugs resulted primarily in no change or attenuated secretion, with some cases of increased secretion, dependent on the cytokine assayed. Among the immunosuppressants evaluated, Hydrocortisone had the most widespread inhibitory effect, while LPS from E. coli O111:B4 had the most potent stimulatory effect. In addition, we also showed that Hydrocortisone or LPS from E. coli O111:B4 affected the migratory and immunosuppressive capacity of BMSCs. Following simulation with Hydrocortisone, BMSC migration was attenuated, and immunosuppressive capacity against T cell proliferation was enhanced, however, the opposite effects were seen with LPS from E. coli O111:B4. Our data suggests that the clinical outcomes of MSC-based therapy are affected by the use of immunosuppressive medication or the presence of endotoxemia in patients.
Highlights
Mesenchymal Stem Cells (MSCs), the best characterized adult stem cells, are defined by the expression of specific markers, namely CD105, CD73, and CD90, lack of expression of CD45, CD34, CD11b, CD19, and HLA-DR surface receptors, and their ability to give rise to osteoblasts, adipocytes, and chondrocytes in vitro [1,2,3]
We found that both immunosuppressive drugs and LPS have distinct effects on the secretomes of bone marrow-derived MSCs (BMSCs) (Figure 1)
BMSC function has already been shown to be modulated in the presence of immunosuppressants as was demonstrated by Popp et al, who showed that the efficacy of BMSCs in inducing long-term acceptance of solid transplant allografts was enhanced in combination with low-dose mycophenolate in a rat heart transplantation model [30]
Summary
Mesenchymal Stem Cells (MSCs), the best characterized adult stem cells, are defined by the expression of specific markers, namely CD105, CD73, and CD90, lack of expression of CD45, CD34, CD11b, CD19, and HLA-DR surface receptors, and their ability to give rise to osteoblasts, adipocytes, and chondrocytes in vitro [1,2,3]. Seminal studies by Di Nicola et al showed that MSCs derived from bone marrow (BM) could inhibit T cell proliferation in a manner which was dependent on transforming growth factor beta (TGFβ1) and hepatocyte growth factor (HGF) secretion [18]. MSCs are recruited to sites of active inflammation or tissue injury where they secrete anti-inflammatory molecules like interleukin-10 (IL-10), HGF, TGFβ1 [19], and indoleamine 2,3-dioxygenase (IDO) [20]. In addition to secreting these regulatory molecules themselves, MSCs influence the secretory profile of other cells to promote and maintain an anti-inflammatory environment [21,22]. In response to IL-12 and IL-18 stimulation, MSCs can prime natural killer (NK) cells for enhanced release of interferon-γ (INF-γ) [23], a cytokine which exhibits both proand anti-inflammatory properties [24,25]. The function of MSCs could be influenced by drugs designed to attenuate immune function and agents such as liposaccharides (LPS)/endotoxins that can augment inflammatory responses [27]
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