Size-Dependent Cortical Compaction Induces Metabolic Adaptation in Mesenchymal Stem Cell Aggregates
Size-Dependent Cortical Compaction Induces Metabolic Adaptation in Mesenchymal Stem Cell Aggregates
复制标题
DOI：
10.1089/ten.tea.2018.0155
复制
发表时间：
2019-04-01
影响因子：
4.1
通讯作者：
Ma, Teng
中科院分区：
文献类型：
--
作者：
Bijonowski, Brent M.;Daraiseh, Susan, I;Ma, Teng
人间充质干细胞（hMSCs）自发组装成三维聚集体，增强了干细胞的特性，并使异型类器官的形成成为可能，这在细胞治疗和组织工程中具有重要意义。虽然向糖酵解方向的代谢重编程是多细胞聚集体的一个显著特征，并且通常将其归因于氧扩散的限制，但最近的研究发现，在hMSC聚集体中，氧张力的有限下降挑战了这一观点。尽管分散细胞群的聚集涉及物理和分子环境的变化，但迄今为止大多数研究都集中在分子梯度上，对聚集细胞命运的生物力学应力研究有限。本研究的目的是通过验证聚集体中大小依赖的压实导致不同的皮质应力，从而诱导代谢重编程的假设，研究聚集体诱导的皮质压实产生的机械梯度如何改变人脂肪来源的间充质干细胞的代谢谱。在此，我们表明，覆盖广泛兴趣范围的多种大小的聚集不会导致缺氧核心形成，而是导致不同水平的皮质压实，这表明应力纤维形成和细胞外基质蛋白沉积之间的平衡，导致相应水平的代谢重构。糖酵解代谢增加，线粒体裂变增加，醛缩酶A释放增加都是皮质压实的结果。格列卫、Wortmannin和Y27632的化学抑制几乎完全消除了皮质应力诱导的糖酵解特性增强。我们的研究结果表明，聚集诱导的生物力学应力在驱动代谢重编程中起着核心作用。本研究表明，多细胞聚集通过机械压实诱导代谢重编程，而不是形成缺氧核心。利用从平面培养中获得的生物力学知识，我们提出了一种新的尺寸依赖性皮质压实的三维（3D）模型，并证明了其在代谢重构中的作用。最终，本研究确定机械压实及其空间梯度是三维人脂肪源性间充质干细胞聚集体发育的关键调控因素和设计参数。
Spontaneous assembly of human mesenchymal stem cells (hMSCs) into three-dimensional aggregates enhances stem cell properties and enables formation of heterotypic organoids, which has significant implication in cell therapy and tissue engineering. Although metabolic reprograming toward glycolysis is a salient feature of multicellular aggregates and it has commonly been attributed to oxygen diffusion limitations, recent studies have instead observed a limited decline in oxygen tension, in hMSC aggregates, challenging this view. Although aggregation of a dispersed cell population involves changes in both the physical and molecular environment, most studies to date have focused on molecular gradients with limited investigation in biomechanical stress on the fate of aggregated cells. The objective of this study is to investigate how the mechanical gradient arising from aggregation-induced cortical compaction alters the metabolic profile of human adipose-derived mesenchymal stem cells by testing the hypothesis that size-dependent compaction in aggregates leads to differential cortical stress, which induces metabolic reprogramming. Herein, we show that aggregation of multiple sizes covering a wide range of interest does not lead to hypoxic core formation but instead varying levels of cortical compaction, indicated by the balance between stress fiber formation and the deposition of extracellular matrix proteins, resulting in corresponding levels of metabolic reconfiguration. Increased glycolytic metabolism, increased mitochondrial fission, and increased release of aldolase A were all observed as a result of cortical compaction. Chemical inhibition with Gleevec, Wortmannin, and Y27632 almost completely abolishes the cortical stress-induced enhancement in glycolytic properties. Our findings demonstrate that aggregation-induced biomechanical stress plays a central role in driving metabolic reprogramming. Impact Statement This study reveals that multicellular aggregation induces metabolic reprogramming via mechanical compaction in lieu of formation of a hypoxic core. Utilizing biomechanical knowledge gained from planar culture, we set forth a novel three-dimensional (3D) model of size-dependent cortical compaction and demonstrated its role in metabolic reconfiguration. Ultimately, this study establishes mechanical compaction and its spatial gradients as key regulatory factors and design parameters in the development of 3D human adipose-derived mesenchymal stem cell aggregates.