力信号在干细胞命运决定过程中的影响

doi:10.12211/2096-8280.2021-066

摘要/Abstract

摘要：

干细胞因具有高效的自我更新能力和分化潜能而具有广泛的应用前景。随着对干细胞命运决定过程的研究不断深入，力信号作为在生物化学因子之外的又一重要影响因素渐渐走入研究者们的视野。对生长环境力学性质的影响效果和作用途径的研究对于深入理解干细胞分化选择的决定机制以及细胞内普遍存在的力学信号传导过程有着十分重要的意义。近年来，合成生物材料的发展极大拓宽了这一领域的研究手段，力学性能可控的合成材料使得条件设计和变量调节更加多元合理。其中，依托于基因重组等技术构建出的蛋白质水凝胶借助其良好的生物相容性和广阔的设计空间为深入挖掘力学性质影响背后的生物学机理提供了更多可能。本文主要介绍了力学信号对干细胞行为的影响效果和作用机理，同时还将介绍各种合成材料在干细胞分化研究领域内的重要应用。对力学信号和细胞行为更加定量化的调控和表征将会是这一领域深入发展的关键，利用合成生物学的方法构建更具针对性的研究工具意义重大。

关键词: 干细胞, 机械力信号, 干性, 分化

Abstract:

Because of their outstanding self-renewing potential and pluripotency, stem cells are believed to have a broad range of applications in various fields such as tissue engineering, drug discovery, gene therapy, and cell therapy. While traditional studies in the field of stem cell fate determination mainly focused on bio-chemical factors, mechanical signals have come into sight of the science community as a crucial role in this area as well. A clearer understanding of the effect of mechanical forces and the mechanotransduction pathways in stem cells are surely helpful for their biomedical and clinic applications. Using synthetic hydrogels with well-defined rigidities as the substrates, the mechano-sensing mechanism and the lineage specification of stem cells have been extensively studied. Recent studies indicate that beyond the effect of substrate rigidity, other mechanical/physical properties, such as stress relaxation, degradation, and porosities, are also critical to stem cell self-renewal and differentiation. However, it remains challenging to control these mechanical parameters of synthetic hydrogels precisely and independently. The advance in synthetic biology may provide novel synthetic protein hydrogels with controllable mechanical responses for the study of force sensing mechanisms and lineage specification of stem cells. In this review, we focus on the impact of mechanical signals on stem cell differentiation and the underlying molecular mechanism. The mechanical signals could be passed down to the nucleus either through a direct mechanical connection of ECM (extracellular matrix)-integrin-FA (focal adhesion)-cytoskeleton or through some signaling molecules. Meanwhile, we introduce some commonly used synthetic hydrogels systems that have been widely used as model systems for stem cell studies. We also highlight different mechanical responses of stem cells cultured in 2D and 3D. It is believed that precise characterization of the cellular behaviors and the mechanical signaling pathways are crucial and can be realized by constructing more specialized hydrogels using advanced synthetic biology tools.

Key words: stem cell, mechanical signals, stemness, differentiation

中图分类号:

宋成治, 孙阳, 曹毅. 力信号在干细胞命运决定过程中的影响[J]. 合成生物学, 2022, 3(4): 781-794.

Chengzhi SONG, Yang SUN, Yi CAO. Effects of mechanical signals on stem cell fate determination[J]. Synthetic Biology Journal, 2022, 3(4): 781-794.

图/表 4

图1 力学信号对干细胞行为造成影响

Fig. 1 Mechanical signals affect stem cells behavior as traditional biochemical signals

图2 不同加力方式处理下的MSC冰冻切片免疫荧光染色照片［（a）～（d）为Agg染色状况，（e）～（h）为Col 2染色状况，（i）～（l）为Col 1染色状况。其中Agg与Col 2均为成软骨指标，Col 1为成骨指标［47］］

Fig. 2 Immunostaining for Col 1, Col 2, and Agg of MSC cryo-sections after different loading regimes[Agg(a～d), Col 2(e～h), Col 1(i～l). Agg and Col 2 are chondrogenic markers while Col 1 are osteogenic markers.]

图3 力学信号传导过程（细胞外力学信号可以通过细胞外基质-整合素-细胞骨架间的连接或借助YAP/TAZ等信号分子的传导进入细胞核中产生作用。而细胞间力学信号则通过E-Cadherin进行介导）

Fig. 3 Schematic diagrams for mechanical signal transduction[External mechanical signal could be passed down to the nucleus either through a direct mechanical connection of ECM (extracellular matrix)-integrin-cytoskeleton or through some signaling molecules such as YAP/TAZ while cellular interaction is mediated through E-Cadherin (LINC: nucleoskeleton and cytoskeleton complex)]

图4 利用Spycatcher/tag化学构建成键密度不同的水凝胶网络［125］

Fig. 4 Building hydrogel network with different bonding density using Spycatcher/tag chemistry[125]

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