Investigating the cardiomyocyte rigidity sensing mechanism with micro patterned surfaces and nanopillars

研究微图案表面和纳米柱的心肌细胞刚性传感机制

• 批准号: BB/S001123/1
• 负责人: Thomas Iskratsch
• 金额: $ 62.51万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS001123%2F1
• 关键词: Investigating; cardiomyocyte; rigidity; sensing; mechanism

Recent discoveries have shown that cells are guided by the stiffness of their environment in a process, called mechanosensing. This influences the fate of the cells in order to form a heart, a blood vessel or other tissue. The stiffness of the heart changes during development, in disease and also during ageing, thereby affecting how well the cells in the heart can beat. However, it is still unclear how the cells in the heart measure the stiffness, or if cells from healthy and diseased hearts can sense it in the same way.In a previous study we found evidence that cells measure the stiffness at specific adhesive structures, known as costameres and focal adhesions through stretchable proteins. If the proteins are stretched, other proteins are activated to remodel certain cellular structures, called actin filaments. The actin filaments come in different varieties. Some of them are specific for cardiomyocytes, while others are also found in other cell types, such as skin or immune cells and needed to anchor the cell, or for migration. On stiff surfaces we find an increased formation of the latter structures and we believe that this will reduce the formation of the former structures (which are needed for the heart to beat). Moreover, based on others and our previous work we hypothesize that the composition of the adhesive structures changes during development and disease. Therefore, stretchable proteins with different characteristics could be located at adhesions at different times.In order to understand how the cells in the heart sense the stiffness we need a clearer picture of what proteins are present at the adhesions and how this affects the formation of the different actin filaments. Here, we want to answer these questions, by placing heart cells on synthetic substrates, which we can produce to have certain stiffnesses, or which we can use to measure the cellular forces. We can also print pattern onto these surfaces, on which the adhesive structures will form. This will allow us to monitor precisely, how much of which protein localizes to the adhesions.Further, we will disturb different signalling pathways that are activated on stiffness comparable to a healthy or diseased heart and observe the changes in the way the cells behave in response to the treatment.Together results from these experiments will lead to a deeper understanding how the heart senses the stiffness. This will allow the design of biomaterials to grow heart cells outside or inside the body to repair injuries from myocardial infarctions or other heart disease.

最近的发现表明，细胞在一个称为机械感知的过程中受到环境刚度的引导。这影响了细胞的命运，以形成心脏，血管或其他组织。心脏的硬度在发育、疾病和衰老过程中发生变化，从而影响心脏细胞的跳动。然而，目前还不清楚心脏细胞如何测量硬度，或者健康和患病心脏的细胞是否可以以同样的方式感知硬度。在之前的研究中，我们发现了细胞通过可拉伸蛋白质测量特定粘附结构（称为costameres和focal adhesion）的硬度的证据。如果蛋白质被拉伸，其他蛋白质被激活以重塑某些细胞结构，称为肌动蛋白丝。肌动蛋白丝有不同的种类。其中一些是心肌细胞特异性的，而另一些也存在于其他细胞类型中，如皮肤或免疫细胞，并需要锚细胞或迁移。在坚硬的表面上，我们发现后者结构的形成增加，我们相信这将减少前者结构的形成（心脏跳动所需的）。此外，根据其他人和我们以前的工作，我们假设，在发展和疾病过程中的粘附结构的组成发生变化。因此，具有不同特征的可拉伸蛋白质可以在不同时间定位于粘连处。为了了解心脏细胞如何感知硬度，我们需要更清楚地了解粘连处存在哪些蛋白质，以及这如何影响不同肌动蛋白丝的形成。在这里，我们想回答这些问题，通过将心脏细胞放置在合成基质上，我们可以生产具有一定刚度的基质，或者我们可以用它来测量细胞力。我们还可以在这些表面上印刷图案，在其上形成粘合剂结构。这将使我们能够精确地监测有多少蛋白质定位于粘连。此外，我们将干扰与健康或患病心脏相似的僵硬时激活的不同信号通路，并观察细胞对治疗的反应方式的变化。这些实验的结果将有助于更深入地了解心脏如何感知僵硬。这将允许设计生物材料在体外或体内生长心脏细胞，以修复心肌梗塞或其他心脏病造成的损伤。

项目成果

Photoelectrochemical imaging of action potentials for single cardiomyocytes through contact force manipulation of organoids

• DOI: 10.1101/2022.09.05.506608
• 发表时间: 2022-09
• 期刊: bioRxiv
• 作者: Rachel Jacques;Bo Zhou;Emilie Marhuenda;Jon Gorecki;Anirban Das;T. Iskratsch;S. Krause

Glioma stem cells invasive phenotype at optimal stiffness is driven by MGAT5 dependent mechanosensing.

• DOI: 10.1186/s13046-021-01925-7
• 发表时间: 2021-04-24
• 期刊: Journal of experimental & clinical cancer research : CR
• 作者: Marhuenda E;Fabre C;Zhang C;Martin-Fernandez M;Iskratsch T;Saleh A;Bauchet L;Cambedouzou J;Hugnot JP;Duffau H;Dennis JW;Cornu D;Bakalara N
• 通讯作者: Bakalara N

Cardiomyocyte mechanical memory is regulated through the talin interactome and DLC1 dependent regulation of RhoA

心肌细胞机械记忆通过talin相互作用组和RhoA的DLC1依赖性调节进行调节

• DOI: 10.1101/2023.07.19.549635
• 发表时间: 2023
• 作者: Marhuenda E

Regulation of cardiomyocyte adhesion and mechanosignalling through distinct nanoscale behaviour of integrin ligands mimicking healthy or fibrotic extracellular matrix.

• DOI: 10.1098/rstb.2022.0021
• 发表时间: 2022-11-21
• 期刊: PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
• 影响因子: 6.3
• 作者: Hawkes, William;Marhuenda, Emilie;Reynolds, Paul;O'Neill, Caoimhe;Pandey, Pragati;Wilson, Darren Graham Samuel;Freeley, Mark;Huang, Da;Hu, Junquiang;Gondarenko, Sasha;Hone, James;Gadegaard, Nikolaj;Palma, Matteo;Iskratsch, Thomas
• 通讯作者: Iskratsch, Thomas

Supplementary Figures and Tables from Regulation of cardiomyocyte adhesion and mechanosignalling through distinct nanoscale behaviour of integrin ligands mimicking healthy or fibrotic extracellular matrix

通过模仿健康或纤维化细胞外基质的整合素配体的独特纳米级行为调节心肌细胞粘附和机械信号传导的补充图和表

• DOI: 10.6084/m9.figshare.20481258
• 发表时间: 2022
• 作者: Hawkes W