Immune Modulatory Mesenchymal Stem Cells Derived from Human Embryonic Stem Cells Through a Trophoblast-Like Stage
Immune Modulatory Mesenchymal Stem Cells Derived from Human Embryonic Stem Cells Through a Trophoblast-Like Stage
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DOI：
10.1002/stem.2242
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发表时间：
2016-02-01
期刊：
影响因子：
5.2
通讯作者：
Xu, Ren-He
中科院分区：
文献类型：
--
作者：
Wang, Xiaofang;Lazorchak, Adam S.;Xu, Ren-He
间充质干细胞(MSCs)在调节炎症和促进组织修复方面具有巨大的临床潜力。人类胚胎干细胞(HESCs)最近被认为是MSCs的一种潜在的优势细胞来源。然而，到目前为止所报道的产生方法在质量和效率上差别很大。在这里，我们描述了一种新的方法，可以在大约11-16天内通过类似滋养细胞的中间阶段快速高效地从人胚胎干细胞中分离出间充质干细胞。我们将这些细胞称为T-MSCs，并表明T-MSCs表达了定义MSCs所需的最低限度的表型和分化潜能。T-MSCs在体外表现出较强的免疫调节活性，能显著抑制共培养的T、B淋巴细胞的增殖。与骨髓间充质干细胞不同，T-MSCs在干扰素-γ作用下不会增加炎性介质的表达。此外，T-MSCs结构性地高水平表达免疫抑制配体PD-L1，并在两种不同的自身免疫性疾病动物模型中诱导出强大而持久的疗效，即葡聚糖硫酸钠诱导的结肠炎和实验性自身免疫性脑脊髓炎，剂量接近于临床试验批准的剂量。总之，我们提出了一种简单而快速的方法来从人胚胎干细胞中获得间充质干细胞，该方法在体外和体内都具有强大的免疫调节特性，可能成为基于骨髓间充质干细胞治疗的一种新的和理想的候选细胞。
Mesenchymal stem/stromal cells (MSCs) have great clinical potential in modulating inflammation and promoting tissue repair. Human embryonic stem cells (hESCs) have recently emerged as a potentially superior cell source for MSCs. However, the generation methods reported so far vary greatly in quality and efficiency. Here, we describe a novel method to rapidly and efficiently produce MSCs from hESCs via a trophoblast-like intermediate stage in approximately 11-16 days. We term these cells "T-MSCs" and show that T-MSCs express a phenotype and differentiation potential minimally required to define MSCs. T-MSCs exhibit potent immunomodulatory activity in vitro as they can remarkably inhibit proliferation of cocultured T and B lymphocytes. Unlike bone marrow MSCs, T-MSCs do not have increased expression of inflammatory mediators in response to IFN gamma. Moreover, T-MSCs constitutively express a high level of the immune inhibitory ligand PD-L1 and elicit strong and durable efficacy in two distinct animal models of autoimmune disease, dextran sulfate sodium induced colitis, and experimental autoimmune encephalomyelitis, at doses near those approved for clinical trials. Together, we present a simple and fast derivation method to generate MSCs from hESCs, which possess potent immunomodulatory properties in vitro and in vivo and may serve as a novel and ideal candidate for MSC-based therapies.