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Temporal impact of substrate mechanics on differentiation of human embryonic stem cells to cardiomyocytes.

机译:底物力学对人类胚胎干细胞向心肌细胞分化的时间影响。

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A significant clinical need exists to differentiate human pluripotent stem cells (hPSCs) into cardiomyocytes, enabling tissue modeling for in vitro discovery of new drugs or cell-based therapies for heart repair in vivo. Chemical and mechanical microenvironmental factors are known to impact the efficiency of stem cell differentiation, but cardiac differentiation protocols in hPSCs are typically performed on rigid tissue culture polystyrene (TCPS) surfaces, which do not present a physiological mechanical setting. To investigate the temporal effects of mechanics on cardiac differentiation, we cultured human embryonic stem cells (hESCs) and their derivatives on polyacrylamide hydrogel substrates with a physiologically relevant range of stiffnesses. In directed differentiation and embryoid body culture systems, differentiation of hESCs to cardiac troponin T-expressing (cTnT+) cardiomyocytes peaked on hydrogels of intermediate stiffness. Brachyury expression also peaked on intermediate stiffness hydrogels at day 1 of directed differentiation, suggesting that stiffness impacted the initial differentiation trajectory of hESCs to mesendoderm. To investigate the impact of substrate mechanics during cardiac specification of mesodermal progenitors, we initiated directed cardiomyocyte differentiation on TCPS and transferred cells to hydrogels at the Nkx2.5/Isl1+ cardiac progenitor cell stage. No differences in cardiomyocyte purity with stiffness were observed on day 15. These experiments indicate that differentiation of hESCs is sensitive to substrate mechanics at early stages of mesodermal induction, and proper application of substrate mechanics can increase the propensity of hESCs to differentiate to cardiomyocytes.
机译:存在着巨大的临床需求,以将人多能干细胞(hPSC)分化为心肌细胞,从而能够进行组织建模,以在体外发现用于体内心脏修复的新药或基于细胞的疗法。已知化学和机械微环境因素会影响干细胞分化的效率,但是hPSC中的心脏分化方案通常是在刚性组织培养聚苯乙烯(TCPS)表面上进行的,该表面没有生理学上的机械作用。为了研究力学对心脏分化的时间影响,我们在具有生理相关硬度范围的聚丙烯酰胺水凝胶基质上培养了人类胚胎干细胞(hESC)及其衍生物。在定向分化和类胚体培养系统中,hESCs向表达心肌肌钙蛋白T(cTnT +)心肌细胞的分化在中等刚度的水凝胶上达到峰值。在定向分化的第1天,中等刚度水凝胶的Brachyury表达也达到高峰,这表明刚度影响了hESCs向中胚层的初始分化轨迹。为了研究中胚层祖细胞心脏规格对基质力学的影响,我们在TCPS上启动了定向心肌细胞分化,并将细胞转移到Nkx2.5 / Isl1 +心脏祖细胞阶段的水凝胶中。在第15天,未观察到心肌细胞纯度与硬度的差异。这些实验表明,在中胚层诱导的早期,hESC的分化对底物力学敏感,适当应用底物力学可以增加hESC分化为心肌细胞的倾向。

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