Soft microenvironments promote the early neurogenic differentiation but not self-renewal of human pluripotent stem cells.
Soft microenvironments promote the early neurogenic differentiation but not self-renewal of human pluripotent stem cells.
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DOI：
10.1039/c2ib20083j
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Schaffer DV
中科院分区：
文献类型：
--
作者：
Keung AJ;Asuri P;Kumar S;Schaffer DV
人类多能干细胞(HPSCs)具有自我更新和分化为任何成体或胎儿细胞类型的能力，在生物学和医学领域具有重要的研究价值。重要的工作已经确定了调节hPSC生物学的生化因素、信号通路和转录网络。然而，最近研究生物物理线索对哺乳动物细胞和成体干细胞影响的工作表明，微环境的机械特性，如僵硬，也可能调节hPSC的行为。虽然已经有几项研究探索了小鼠胚胎干细胞(MESCs)的这种机械调节，但推断这些发现并由此探索它们在hPSCs中的生物医学意义一直是具有挑战性的。例如，目前尚不清楚是否可以通过提供组织模拟僵硬线索来驱动hPSCs沿着给定的组织谱系发展。在这里，我们通过研究微环境僵硬对hPSC神经发生的调控来解决这个悬而未决的问题。我们发现，与过去对mESCs的研究相反，在体外增加细胞外基质(ECM)的硬度可以增加hPSC细胞和集落铺展面积，但不会改变自我更新。然而，硬度与神经组织相似的较软的ECM可促进早期神经外胚层的形成。这种神经外胚层的机械敏感性增加只需要一个短暂的5天软僵硬“脉冲”，这转化为下游总神经元以及与治疗相关的多巴胺能神经元的增加。这些发现进一步突出了mESCs和hPSCs之间的重要差异，并对未来生物材料的设计以及我们对早期胚胎发育的理解都有意义。
Human pluripotent stem cells (hPSCs) are of great interest in biology and medicine due to their ability to self-renew and differentiate into any adult or fetal cell type. Important efforts have identified biochemical factors, signaling pathways, and transcriptional networks that regulate hPSC biology. However, recent work investigating the effect of biophysical cues on mammalian cells and adult stem cells suggests that the mechanical properties of the microenvironment, such as stiffness, may also regulate hPSC behavior. While several studies have explored this mechanoregulation in mouse embryonic stem cells (mESCs), it has been challenging to extrapolate these findings and thereby explore their biomedical implications in hPSCs. For example, it remains unclear whether hPSCs can be driven down a given tissue lineage by providing tissue-mimetic stiffness cues. Here we address this open question by investigating the regulation of hPSC neurogenesis by microenvironmental stiffness. We find that increasing extracellular matrix (ECM) stiffness in vitro increases hPSC cell and colony spread area but does not alter self-renewal, in contrast to past studies with mESCs. However, softer ECMs with stiffnesses similar to that of neural tissue promote the generation of early neural ectoderm. This mechanosensitive increase in neural ectoderm requires only a short 5-day soft stiffness “pulse,” which translates into downstream increases in both total neurons as well as therapeutically relevant dopaminergic neurons. These findings further highlight important differences between mESCs and hPSCs and have implications for both the design of future biomaterials as well as our understanding of early embryonic development.
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影响因子：
64.8
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
通讯作者：
Studer, Lorenz
人和小鼠胚胎干细胞中的联合结合鉴定了早期胚胎发育中活跃的保守增强子。
影响因子：
4.3
作者：
Göke J;Jung M;Behrens S;Chavez L;O'Keeffe S;Timmermann B;Lehrach H;Adjaye J;Vingron M
通讯作者：
Vingron M
影响因子：
3.7
作者：
Chowdhury F;Li Y;Poh YC;Yokohama-Tamaki T;Wang N;Tanaka TS
通讯作者：
Tanaka TS
影响因子：
64.8
作者：
Brons, I. Gabrielle M.;Smithers, Lucy E.;Vallier, Ludovic
通讯作者：
Vallier, Ludovic
影响因子：
23.9
作者：
Nichols, Jennifer;Smith, Austin
通讯作者：
Smith, Austin