Immunomodulatory Effect of MSC on B Cells Is Independent of Secreted Extracellular Vesicles
Immunomodulatory Effect of MSC on B Cells Is Independent of Secreted Extracellular Vesicles
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DOI：
10.3389/fimmu.2019.01288
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发表时间：
2019-06-06
影响因子：
7.3
通讯作者：
Franquesa, Marcella
中科院分区：
文献类型：
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作者：
Carreras-Planella, Laura;Monguio-Tortajada, Marta;Franquesa, Marcella
间充质干细胞或基质细胞（MSC）已被证明具有对B细胞活化的免疫调节特性，并通过依赖于细胞接触和分泌因子的双重作用机制诱导调节性B细胞（布雷格）。其中之一是MSC衍生的细胞外囊泡（EV），介导细胞通讯并通常反映起源细胞表型的膜纳米囊泡。MSC-EV可以类似于MSC功能，并且被认为是基于MSC的免疫调节治疗的改进替代方案。在本工作中，我们专注于MSC分泌的因子，旨在阐明MSC-EV在B细胞免疫调节中的假定作用。使用尺寸排阻色谱法（SEC）从MSC条件培养基（CM）中分离EV和可溶性蛋白富集级分（PF），并将它们调节B细胞活化、诱导布雷格和B细胞增殖的能力与整个MSC的能力进行比较。与MSC或未分级的CM共培养诱导了B细胞上的幼稚和CD 24（hi）、CD 38（hi）、IL-10产生（布雷格）表型，同时不影响增殖。MSC-PF与MSC的作用相当，诱导幼稚表型，即使它们不诱导向CD 24（hi）CD 38（hi）群体的转变，MSC-PF也促进了B细胞产生IL-10。相反，MSC-EV不能促进幼稚B细胞和减少记忆B细胞。MSC-EV诱导CD 24（hi）CD 38（hi）B细胞的程度与MSC相似，但不是真正的B细胞，因为它们不产生IL-10。我们的研究结果表明，MSC对B细胞的调节部分是由EV以外的可溶性因子介导的。
Mesenchymal stem or stromal cells (MSC) have proven immunomodulatory properties toward B cell activation and induce regulatory B cells (Breg), through a dual mechanism of action that relies both on cell contact and secreted factors. One of them are MSC-derived extracellular vesicles (EVs), membrane nanovesicles that mediate cell communication and typically reflect the phenotype of the cell of origin. MSC-EVs could resemble MSC functions, and are being contemplated as an improved alternative to the MSC-based immunomodulatory therapy. In the present work, we focused on the factors secreted by MSC and aimed to elucidate the putative role of MSC-EVs in the immunomodulation of B cells. EVs and soluble protein-enriched fractions (PF) were isolated from MSC-conditioned medium (CM) using size-exclusion chromatography (SEC) and their capacity to modulate B cell activation, induction of Breg and B cell proliferation was compared to that of the whole MSCs. Co-culture with MSC or unfractionated CM induced naive and CD24(hi)CD38(hi), IL-10 producing (Breg) phenotypes on B cells while not affecting proliferation. MSC-PF had a comparable effect to MSCs, inducing a naive phenotype, and even though they did not induce the shift toward a CD24(hi)CD38(hi) population, MSC-PF fostered IL-10 production by B cells. Conversely, MSC-EVs failed to promote naive B cells and to reduce memory B cells. MSC-EVs induced CD24(hi)CD38(hi) B cells to a similar extent of that of MSC, but not bona fide Bregs since they did not produce IL-10. Our results show that B cell modulation by MSC is partially mediated by soluble factors other than EVs.