Del Fattore Andrea, Luciano Rosa, Pascucci Luisa, Goffredo Bianca Maria, Giorda Ezio, Scapaticci Margherita, Fierabracci Alessandra, Muraca Maurizio
Regenerative Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
Cell Transplant. 2015;24(12):2615-27. doi: 10.3727/096368915X687543. Epub 2015 Feb 18.
The immunomodulatory activity of mesenchymal stem cells (MSCs) is largely mediated by paracrine factors. We have recently shown that the immunosuppressive effects of MSCs on B lymphocytes in peripheral blood mononuclear cell (PBMC) culture can be reproduced by extracellular vesicles (EVs) isolated from MSC culture supernatants. Here we investigated the effect of bone marrow-derived MSC-EVs on T cells on PBMC cultures stimulated with anti-CD3/CD28 beads. Stimulation increased the number of proliferating CD3(+) cells as well as of regulatory T cells (Tregs). Coculture with MSCs inhibited the proliferation of CD3(+) cells, with no significant changes in apoptosis. Addition of MSC-EVs to PBMCs did not affect proliferation of CD3(+) cells, but induced the apoptosis of CD3(+) cells and of the CD4(+) subpopulation and increased the proliferation and the apoptosis of Tregs. Moreover, MSC-EV treatment increased the Treg/Teff ratio and the immunosuppressive cytokine IL-10 concentration in culture medium. The activity of indoleamine 2,3-dioxygenase (IDO), an established mediator of MSC immunosuppressive effects, was increased in supernatants of PBMCs cocultured with MSCs, but was not affected by the presence of MSC-EVs. MSC-EVs demonstrate immunomodulatory effects on T cells in vitro. However, these effects and the underlying mechanisms appear to be different from those exhibited by their cells of origin.
间充质干细胞（MSCs）的免疫调节活性很大程度上由旁分泌因子介导。我们最近发现，从MSC培养上清液中分离出的细胞外囊泡（EVs）能够重现MSCs对外周血单核细胞（PBMC）培养物中B淋巴细胞的免疫抑制作用。在此，我们研究了骨髓来源的MSC-EVs对用抗CD3/CD28磁珠刺激的PBMC培养物中T细胞的影响。刺激增加了增殖性CD3(+)细胞以及调节性T细胞（Tregs）的数量。与MSCs共培养抑制了CD3(+)细胞的增殖，而细胞凋亡无显著变化。向PBMC中添加MSC-EVs并不影响CD3(+)细胞的增殖，但诱导了CD3(+)细胞和CD4(+)亚群的凋亡，并增加了Tregs的增殖和凋亡。此外，MSC-EV处理增加了培养物中的Treg/Teff比值和免疫抑制细胞因子IL-10的浓度。吲哚胺2,3-双加氧酶（IDO）是MSCs免疫抑制作用的既定介质，其活性在与MSCs共培养的PBMC上清液中增加，但不受MSC-EVs存在的影响。MSC-EVs在体外对T细胞表现出免疫调节作用。然而，这些作用及其潜在机制似乎与其来源细胞所表现出的不同。
