Mesenchymal Stem Cell Population Derived from Human Pluripotent Stem Cells Displays Potent Immunomodulatory and Therapeutic Properties
Mesenchymal Stem Cell Population Derived from Human Pluripotent Stem Cells Displays Potent Immunomodulatory and Therapeutic Properties
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DOI：
10.1089/scd.2013.0554
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发表时间：
2014-07-15
影响因子：
4
通讯作者：
Lanza, Robert
中科院分区：
文献类型：
--
作者：
Kimbrel, Erin A.;Kouris, Nicholas A.;Lanza, Robert
间充质干细胞（MSC）正在多种人类疾病中进行测试；然而，效力的丧失和质量不稳定严重限制了它们的使用。为了克服这些问题，我们利用一种称为成血管细胞的发育前体作为中间细胞类型，从人胚胎干细胞 (hESC) 中衍生出高效且可补充的 MSC 群体。该方法避免了其他 hESC-MSC 衍生方法所需的劳动密集型手工挑选、刮擦和分类的需要。此外，与之前关于 hESC-MSC 的报道不同，我们系统地评估了它们的免疫调节特性和体内效力。正如预期的那样，它们动态地分泌一系列生物活性因子，表现出酶活性，并抑制由同种异体细胞或促有丝分裂刺激诱导的 T 细胞增殖。然而，它们还表现出独特的免疫表型特性，以及比骨髓来源的 MSC 更小的尺寸和超过 30,000 倍的增殖能力。此外，这是第一份证明 hESC-MSC 可以抑制树突状细胞 CD83 上调和 IL-12p70 分泌并增强白细胞介素 2 (IL-2) 诱导的调节性 T 细胞群的报告。这也是第一份表明 hESC-MSC 在两种不同的自身免疫性疾病模型中具有治疗功效的报告，包括显着增加狼疮易发小鼠的存活率和减轻葡萄膜炎自身免疫模型的症状。我们的数据表明，这种新型且具有治疗活性的 MSC 群体可以克服困扰 MSC 在再生医学中使用的许多障碍，并作为当前 MSC 来源的可扩展替代品。
Mesenchymal stem cells (MSCs) are being tested in a wide range of human diseases; however, loss of potency and inconsistent quality severely limit their use. To overcome these issues, we have utilized a developmental precursor called the hemangioblast as an intermediate cell type in the derivation of a highly potent and replenishable population of MSCs from human embryonic stem cells (hESCs). This method circumvents the need for labor-intensive hand-picking, scraping, and sorting that other hESC-MSC derivation methods require. Moreover, unlike previous reports on hESC-MSCs, we have systematically evaluated their immunomodulatory properties and in vivo potency. As expected, they dynamically secrete a range of bioactive factors, display enzymatic activity, and suppress T-cell proliferation that is induced by either allogeneic cells or mitogenic stimuli. However, they also display unique immunophenotypic properties, as well as a smaller size and >30,000-fold proliferative capacity than bone marrow-derived MSCs. In addition, this is the first report which demonstrates that hESC-MSCs can inhibit CD83 up-regulation and IL-12p70 secretion from dendritic cells and enhance regulatory T-cell populations induced by interleukin 2 (IL-2). This is also the first report which shows that hESC-MSCs have therapeutic efficacy in two different autoimmune disorder models, including a marked increase in survival of lupus-prone mice and a reduction of symptoms in an autoimmune model of uveitis. Our data suggest that this novel and therapeutically active population of MSCs could overcome many of the obstacles that plague the use of MSCs in regenerative medicine and serve as a scalable alternative to current MSC sources.