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Bio-Design and Manufacturing  2022 Vol.5 No.4 P.714-728

http://doi.org/10.1007/s42242-022-00209-z


Mechanical stretching of 3D hydrogels for neural stem cell differentiation


Author(s):  Quanjing Mei, Ho-Yin Yuen & Xin Zhao

Affiliation(s):  Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China

Corresponding email(s):   xin.zhao@polyu.edu.hk

Key Words:  Mechanical property, Tensile stretching, Hydrogels, Neural differentiation, 3D cell culture


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Quanjing Mei, Ho-Yin Yuen & Xin Zhao. Mechanical stretching of 3D hydrogels for neural stem cell differentiation[J]. Journal of Zhejiang University Science D, 2022, 5(4): 714-728.

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Abstract: 
While it is known that mechanical dynamics are influential in neural differentiation for critical processes like neurogenesis or neurodegeneration, studies on neural stem cell therapies usually focus on biochemical interactions rather than mechanical aspects, frequently resulting in low efficacy and unfulfilled potential. Therefore, current studies are attempting to elucidate the effect of mechanical stimulus on neural performance using conventional two-dimensional (2D) planar substrates. Yet, these 2D substrates fail to capture the defining three-dimensional (3D) characteristics of the in vivo neural stem cell environment. To complete this research gap, we synthesized a series of soft and elastic 3D hydrogels to mimic the neural tissue mechanical environment for 3D cell culture, using long-chain polyethylene glycol diacrylate (PEGDA) and gelatin-methacryloyl (GelMA). By varying the concentration of the polymer, we obtained biomimicking hydrogels with a tensile modulus as low as 10 kPa and a compressive modulus as low as 0.8 kPa. The in vitro results demonstrated that GelMA-PEGDA hydrogels have the high biocompatibility required to support neural cell growth, proliferation, and differentiation, as well as neurite outgrowth. We then studied the effect of mechanical stretching on the behaviors of neural cells and observed that mechanical stretching could significantly enhance neurite extension and axon elongation. In addition, the neurites were more directionally oriented to the stretching direction. Immunocytochemistry and relative gene expression data also suggested that mechanical tension could upregulate the expression of neural differentiation protein and genes, including GFAP and ?III-Tubulin. Overall, this study shows that in addition to the specific mechanical properties of GelMA-PEGDA that improve neural differentiation towards specific lineages, hydrogel stretching is also a potentially attractive strategy to improve the therapeutic outcomes of neural stem cell therapies.

香港理工大学赵昕、梅全静等 | 机械拉伸3D水凝胶诱导神经干细胞的分化

本研究论文聚焦3D力学微环境诱导神经干细胞(NSC)的定向分化。NSC的定向分化对神经再生研究和神经系统损伤的治疗起着重要作用,在众多影响神经分化的因素中,力学微环境是关键的要素之一。既往的神经力学研究多局限于二维环境(2D),即使用2D基质来阐明机械刺激对神经分化的影响,然而这些2D基质难以模拟体内NSC三维环境(3D)。鉴于此,本研究制备了一系列柔软且有弹性的3D水凝胶来模拟神经三维力学微环境,并研究了基质刚度及机械拉伸对NSC分化的影响。研究者以甲基丙烯酸酐化明胶(GelMA)和长链聚乙二醇二丙烯酸酯(PEGDA)为基础,通过调整两者的比例得到了不同模量的仿生水凝胶。研究表明,GelMA-PEGDA水凝胶具有高生物相容性,可支持NSC在3D环境中生长、增殖、分化。通过观察NSC在不同基质刚度的水凝胶中的状态,研究者发现NSC在相对较硬的基质中更倾向于分化成为胶质细胞,而在相对较软的基质中更倾向于分化成为神经细胞。进一步的3D拉伸实验证明,机械拉伸可以显著增强NSC的分化和轴突的生长,而且神经轴突更倾向于向拉伸方向延伸。免疫细胞化学和相关基因表达也表明,机械拉伸可以上调神经分化蛋白和基因的表达。总体而言,本文不仅丰富了NSC在3D力学微环境中定向分化的研究,而且为神经干细胞治疗的有效性和可行性提供了基础。

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