A Clinical Indications Prediction Scale Based on TWIST1 for Human Mesenchymal Stem Cells.
A Clinical Indications Prediction Scale Based on TWIST1 for Human Mesenchymal Stem Cells.
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DOI：
10.1016/j.ebiom.2015.12.020
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发表时间：
2016-02
期刊：
影响因子：
11.1
通讯作者：
Phinney DG
中科院分区：
文献类型：
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作者：
Boregowda SV;Krishnappa V;Haga CL;Ortiz LA;Phinney DG
除了干细胞/祖细胞的特性外，间充质干细胞（MSCs）还表现出强大的效应（血管生成、抗炎、免疫调节）功能，这些功能在本质上主要是旁分泌的。人们普遍认为，效应功能是MSCs大部分治疗潜力的基础，并且独立于它们的干细胞/祖细胞特性。在这里，我们证明了干细胞/祖细胞和效应细胞功能在细胞水平上由转录因子Twist1协调调节，并根据层次模型在群体中指定。我们进一步表明，通过遗传方法或暴露于广泛使用的培养补充剂（包括成纤维细胞生长因子2 （Ffg2）和干扰素γ (ifn - γ)）来操纵Twist1水平，可以以可预测的方式改变细胞和体内实验中MSC的功效。因此，通过机械地将干细胞/祖细胞和效应功能联系起来，我们的研究以MSC层次结构的形式提供了一个统一的框架，该框架可以模拟种群的功能复杂性。利用这一框架，我们开发了一个临床适应症预测（CLIP）量表，预测供体间的异质性和培养条件如何影响MSC群体对不同疾病适应症的治疗效果。间充质干细胞具有干细胞/祖细胞和效应细胞（血管生成、抗炎、免疫调节）功能。Twist1协调调节茎/祖细胞和效应细胞的功能，这些功能在种群中是分层指定的。Twist1水平预测间充质干细胞对不同疾病适应症治疗效果的群体间差异。间充质干细胞正在人类临床试验中被评估用于治疗缺血性、炎症性和免疫性疾病。然而，大多数已完成的试验都产生了次优结果，因为无法预测不同供体群体的效力，这些群体在功能上是异质的。我们证明MSCs的临床相关生物学活性是由转录因子Twist1协调调节的。此外，我们发现TWIST1水平可靠地预测了人群在血管生成、抗炎和免疫调节活性方面的差异，并以此为基础开发了临床适应症预测（CLIP）量表。通过预测MSC群体对不同疾病适应症的效力，CLIP量表有望显著改善基于MSC的临床试验结果。
In addition to their stem/progenitor properties, mesenchymal stem cells (MSCs) also exhibit potent effector (angiogenic, antiinflammatory, immuno-modulatory) functions that are largely paracrine in nature. It is widely believed that effector functions underlie most of the therapeutic potential of MSCs and are independent of their stem/progenitor properties. Here we demonstrate that stem/progenitor and effector functions are coordinately regulated at the cellular level by the transcription factor Twist1 and specified within populations according to a hierarchical model. We further show that manipulation of Twist1 levels by genetic approaches or by exposure to widely used culture supplements including fibroblast growth factor 2 (Ffg2) and interferon gamma (IFN-gamma) alters MSC efficacy in cell-based and in vivo assays in a predictable manner. Thus, by mechanistically linking stem/progenitor and effector functions our studies provide a unifying framework in the form of an MSC hierarchy that models the functional complexity of populations. Using this framework, we developed a CLinical Indications Prediction (CLIP) scale that predicts how donor-to-donor heterogeneity and culture conditions impact the therapeutic efficacy of MSC populations for different disease indications. Mesenchymal stem cells exhibit stem/progenitor and effector (angiogenic, anti-inflammatory, immuno-modulatory) functions. Twist1 coordinately regulates stem/progenitor and effector functions, which are specified hierarchically in populations. Twist1 levels predict inter-population differences in therapeutic efficacy of mesenchymal stem cells for different disease indications. Mesenchymal stem cells are being evaluated in human clinical trials for treating ischemic, inflammatory, and immunological diseases. However, most completed trials have yielded suboptimal outcomes due to the inability to predict the potency of different donor populations, which are functionally heterogeneous. We demonstrate that clinically relevant biological activities of MSCs are coordinately regulated by the transcription factor Twist1. Furthermore, we showed that TWIST1 levels reliably predict differences in the angiogenic, anti-inflammatory, and immuno-modulatory activity of populations and as such used it to develop a Clinical Indications Prediction (CLIP) scale. By predicting potency of MSC populations for different disease indications the CLIP scale is expected to dramatically improve MSC-based clinical trial outcomes.