Tissue Mechanics in Growth and Regeneration

生长和再生中的组织力学

• 批准号: MR/L009056/1
• 负责人: Yanlan Mao
• 金额: $ 152.72万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL009056%2F1
• 关键词: Tissue; Mechanics; Growth; Regeneration

As we grow from an embryo to an adult, how do our tissues and organs reach their final correct size and shape? How do they know when to stop growing? The control of normal organ growth is highly complex, but highly important, as when the control system fails, this causes overgrowth, and frequently cancer. When our tissues and organs are damaged by injury, they can often repair themselves in a precisely controlled way to recover their original size and shape. However, this precise repair mechanism also often fails, leading to scarring, fibrosis or tumour like over-growths. Can we understand the regenerative process from a new perspective in order to design new therapies for wound healing and diseases where growth is altered?These are the questions I would like to answer with my research. Cells can communicate by sending chemical signals to each other. Although chemical control of growth has been widely studied, my novel angle of research is to ask whether physical mechanical forces can influence tissue growth - if you were to stretch or compress tissues, can you alter their growth patterns, change their final size, or improve their regenerative capacity?There is increasing evidence that a tissue's mechanical environment can have a huge impact on the growth of cells. For example, astronauts in space start to lose their bone mass, because there is no mechanical tension from gravity to stimulate bone formation. Despite the large amount of evidence around us that a tissue's mechanical environment is very important for its growth, surprisingly little work has been done to investigate this at the cell/tissue level. I would like to understand how forces control growth, and eventually apply it to design novel physical treatments for cancer therapy, regenerative medicine, and tissue engineering. This work will require scientists from many backgrounds - biologists, physicists, and engineers - to work together as a team. This interdisciplinary approach will without doubt generate many exciting and creative ideas, and inspire scientists as they learn from each other.Many biologists have successfully used the wing of the fruit fly as a model to study growth control, revealing many parallels to human growth control. I plan to exploit this model tissue and develop techniques that will allow me to monitor its growth over time, both during its normal development, and after wounding. I also plan to develop a novel technique to stretch and compress this tissue, and then observe what happens to its final size and shape. I hope to put all these data, the pieces of a puzzle, together, into a mathematical/computer model and eventually make a virtual wing. In the model, I'll be able to compare the relative importance of the different control mechanisms, something that's quite hard to do using experiments alone. I will also be able to simulate disease conditions, and treatment strategies, before trying them in real organisms/tissues. I anticipate that this combinatorial approach will greatly increase our efficiency in understanding normal and diseased tissue growth.

当我们从胚胎成长为成年人时，我们的组织和器官是如何达到最终正确的大小和形状的？他们怎么知道什么时候停止生长？正常器官生长的控制非常复杂，但非常重要，因为当控制系统失败时，这会导致过度生长，并经常导致癌症。当我们的组织和器官因受伤而受损时，它们通常可以以精确控制的方式进行自我修复，以恢复其原始大小和形状。然而，这种精确的修复机制也经常失败，导致疤痕，纤维化或肿瘤样过度生长。我们能否从新的角度理解再生过程，以便为伤口愈合和生长改变的疾病设计新的疗法？这些都是我想用我的研究来回答的问题。细胞可以通过相互发送化学信号进行通信。虽然生长的化学控制已经被广泛研究，但我的研究视角是问物理机械力是否会影响组织生长-如果你拉伸或压缩组织，你能改变它们的生长模式，改变它们的最终大小，或者提高它们的再生能力吗？越来越多的证据表明，组织的机械环境可以对细胞的生长产生巨大影响。例如，宇航员在太空中开始失去骨量，因为没有来自重力的机械张力来刺激骨骼形成。尽管我们周围有大量的证据表明组织的机械环境对其生长非常重要，但令人惊讶的是，在细胞/组织水平上研究这一点的工作很少。我想了解力是如何控制生长的，并最终将其应用于设计癌症治疗，再生医学和组织工程的新型物理治疗方法。这项工作将需要来自许多背景的科学家-生物学家，物理学家和工程师-作为一个团队一起工作。这种跨学科的方法无疑会产生许多令人兴奋和创造性的想法，并激励科学家们互相学习。许多生物学家已经成功地利用果蝇的翅膀作为模型来研究生长控制，揭示了许多与人类生长控制相似的地方。我计划利用这个模型组织，并开发技术，使我能够监测它随着时间的推移，无论是在其正常发育期间，还是在受伤后。我还计划开发一种新的技术来拉伸和压缩这种组织，然后观察它最终的大小和形状会发生什么变化。我希望把所有这些数据，拼图的碎片，放在一起，进入一个数学/计算机模型，并最终作出一个虚拟的翅膀。在这个模型中，我将能够比较不同控制机制的相对重要性，这是很难单独使用实验来做的。我也将能够模拟疾病的条件，和治疗策略，然后尝试他们在真实的生物体/组织。我预计这种组合方法将大大提高我们理解正常和病变组织生长的效率。

项目成果

Polarization of Myosin II refines tissue material properties to buffer mechanical stress

肌球蛋白 II 的极化可改善组织材料特性以缓冲机械应力

• DOI: 10.1101/241497
• 发表时间: 2017
• 作者: Duda M

A combination of Notch signaling, preferential adhesion and endocytosis induces a slow mode of cell intercalation in the Drosophila retina.

Notch信号，优先粘附和内吞作用的结合诱导果蝇视网膜的细胞插入模式缓慢。

• DOI: 10.1242/dev.197301
• 发表时间: 2021-05-15
• 期刊: Development (Cambridge, England)
• 作者: Blackie L;Tozluoglu M;Trylinski M;Walther RF;Schweisguth F;Mao Y;Pichaud F
• 通讯作者: Pichaud F

Inter-cellular forces orchestrate contact inhibition of locomotion.

• DOI: 10.1016/j.cell.2015.02.015
• 发表时间: 2015-04-09
• 期刊: Cell
• 影响因子: 64.5
• 作者: Davis JR;Luchici A;Mosis F;Thackery J;Salazar JA;Mao Y;Dunn GA;Betz T;Miodownik M;Stramer BM
• 通讯作者: Stramer BM

EpiTools: An Open-Source Image Analysis Toolkit for Quantifying Epithelial Growth Dynamics.

• DOI: 10.1016/j.devcel.2015.12.012
• 发表时间: 2016-01-11
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Heller D;Hoppe A;Restrepo S;Gatti L;Tournier AL;Tapon N;Basler K;Mao Y
• 通讯作者: Mao Y

Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics.

• DOI: 10.1038/s41590-022-01272-5
• 发表时间: 2022-08
• 期刊: NATURE IMMUNOLOGY
• 影响因子: 30.5
• 作者: Horsnell, Harry L.;Tetley, Robert J.;De Belly, Henry;Makris, Spyridon;Millward, Lindsey J.;Benjamin, Agnesska C.;Heeringa, Lucas A.;de Winde, Charlotte M.;Paluch, Ewa K.;Mao, Yanlan;Acton, Sophie E.
• 通讯作者: Acton, Sophie E.