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Mesenchymal Stem Cell Population Derived from Human Pluripotent Stem Cells Displays Potent Immunomodulatory and Therapeutic Properties

机译:人多能干细胞衍生的间充质干细胞群体显示出强大的免疫调节和治疗特性。

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摘要

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.
机译:间充质干细胞(MSC)正在各种人类疾病中进行测试;但是,效价损失和质量不一致严重限制了它们的使用。为了克服这些问题,我们从人类胚胎干细胞(hESC)衍生出高度有效且可补充的MSC群体中,利用了称为成血管细胞的发育前体作为中间细胞类型。该方法避免了其他hESC-MSC派生方法所需的劳动强度大的手工挑选,抓取和分类工作。而且,与先前关于hESC-MSC的报道不同,我们已经系统地评估了它们的免疫调节特性和体内效力。如预期的那样,它们动态分泌一系列生物活性因子,显示酶活性,并抑制同种异体细胞或促有丝分裂刺激诱导的T细胞增殖。但是,它们还显示出独特的免疫表型特性,并且比骨髓来源的MSC具有更小的尺寸和> 30,000倍的增殖能力。此外,这是第一个证明hESC-MSC可以抑制树突状细胞CD83上调和IL-12p70分泌并增强白介素2(IL-2)诱导的调节性T细胞群体的报道。这也是首次报道,hESC-MSC在两种不同的自身免疫性疾病模型中具有治疗功效,包括易患狼疮小鼠的存活期显着增加和葡萄膜炎的自身免疫性模型中的症状减轻。我们的数据表明,这种新颖且具有治疗活性的MSC群体可以克服许多困扰在再生医学中使用MSC的障碍,并且可以作为当前MSC来源的可扩展替代方案。

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