机械转导动力学模型的数值分析揭示了由细胞外基质介导的间质干细胞命运振荡的同宿分岔
Numerical analysis of a mechanotransduction dynamical model reveals homoclinic bifurcations of extracellular matrix mediated oscillations of the mesenchymal stem cell fate
AI总结：
研究通过数值分析揭示了机械转导模型中细胞外基质介导的间质干细胞命运振荡的同宿分岔现象，探讨了细胞分化中的非线性行为及多稳态特性。
摘要：
我们对一个近似描述间质干细胞分化为神经元、脂肪细胞、心肌细胞和成骨细胞动态的机械转导模型进行了单参数和双参数数值分岔分析。在分析中，我们将细胞外基质的刚度和与正反馈机制相关的参数作为分岔参数，这些正反馈机制上调了YAP/TAZ转录调控因子（TRs）和细胞粘附面积的产生。我们的分析揭示了细胞分化的丰富非线性行为，包括滞回和多稳态区域、有效粘附面积的稳定振荡、与脂肪生成命运相关的YAP/TAZ TRs和PPARγ受体的振荡，以及中断较高振幅振荡的同宿分岔。对产生振荡模式的Andronov-Hopf点的双参数分岔分析预测了这些振荡模式在软细胞外基质（<1kPa）中的存在，这一区域有利于神经生成和脂肪生成细胞命运。此外，在这些区域中，分析揭示了同宿分岔的存在，导致细胞-基质粘附的稳定振荡突然向弱粘附和高表达Tubulin beta-3链基因的表达转移，从而促进从脂肪生成到神经生成命运的相变。
英文摘要：
We perform one and two-parameter numerical bifurcation analysis of a mechanotransduction model approximating the dynamics of mesenchymal stem cell differentiation into neurons, adipocytes, myocytes and osteoblasts. For our analysis, we use as bifurcation parameters the stiffness of the extracellular matrix and parameters linked with the positive feedback mechanisms that up-regulate the production of the YAP/TAZ transcriptional regulators (TRs) and the cell adhesion area. Our analysis reveals a rich nonlinear behaviour of the cell differentiation including regimes of hysteresis and multistability, stable oscillations of the effective adhesion area, the YAP/TAZ TRs and the PPAR$γ$ receptors associated with the adipogenic fate, as well as homoclinic bifurcations that interrupt relatively high-amplitude oscillations abruptly. The two-parameter bifurcation analysis of the Andronov-Hopf points that give birth to the oscillating patterns predicts their existence for soft extracellular substrates ($<1kPa$), a regime that favours the neurogenic and the adipogenic cell fate. Furthermore, in these regimes, the analysis reveals the presence of homoclinic bifurcations that result in the sudden loss of the stable oscillations of the cell-substrate adhesion towards weaker adhesion and high expression levels of the gene encoding Tubulin beta-3 chain, thus favouring the phase transition from the adipogenic to the neurogenic fate.
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