Multiscale modeling of epithelial tissue dynamics and engineering

最近有报道称，利用胚胎干细胞培育出人类视网膜和脑组织，在实验室中培育人造组织和器官的前景令人兴奋不已。然而，在广泛的临床应用成为现实之前，仍需克服巨大的科学和技术障碍。可以植入人造组织来恢复、修复和改善衰竭的自然器官的功能，这对医疗保健的潜在好处是巨大的，但挑战也是艰巨的。 进展将取决于两个领域的新研究：发育生物学和生物材料工程。这里提出的研究寻求一种非常规方法，将发育生物学的分子遗传信息与上皮组织力学的工程知识相结合。这种整合的动机是生物组织不仅根据遗传蓝图生长，而且还受到物理环境中的机械力和变形的影响。从机械角度来看，软组织的行为方式通常类似于复杂流体和软固体。该提案的中心思想是将针对复杂流体和软物质开发的计算方法转化为上皮问题动力学和生长中的一类新问题。 上皮是指包围器官和胚胎的皮肤。它也是胚胎早期发育过程中折叠形成内脏器官的关键结构。为了定量理解这些过程，我们开发了一个数学模型，将细胞尺度和更大的组织尺度联系起来。该模型的一个关键特征是正确捕获两个尺度之间的信息交换。例如，皮肤组织上的持续压力往往会引发形成每个细胞骨架的聚合物的结构变化，并溶解相邻细胞之间的粘合连接。因此整个组织会变形或“流动”。作为回报，细胞内的小规模生物化学会产生控制细胞分裂和死亡的信号蛋白，这些事件最终会大规模地反馈到组织的整体行为。我们进一步对组织生长的各种场景进行计算机模拟，采用我们为复杂流体、界面和软膜动力学开发的广泛数值工具包。 从科学角度来看，我们预计这项研究将产生两个主要成果。首先是为定量理解上皮动力学奠定基础。特别是，我们希望阐明机械力和变形如何改变组织的特性并影响其在实验室条件下生长的能力。二是培养解决组织工程“逆问题”的能力。这是制定最佳实验条件和方案的能力，从而产生组织或器官所需的形态。这些成果将是实现定制人造器官目标的重大进步，为加拿大及其他地区带来深远的医疗保健效益。 这项研究的一个不太明显但同样重要的好处是对这一新兴领域的年轻科学家进行专门培训。他们将接触到前沿的跨学科研究，利用物理和工程工具来研究生物学并为医学提供信息。这将使他们为未来几十年不断扩大的研发领域做好准备。

The prospect of growing artificial tissues and organs in the lab is generating much excitement, with the recent reports of human retina and brain tissues grown from embryonic stem cells. However, great scientific and technical barriers remain to be surmounted before widespread clinical use becomes reality. The potential benefits for health care, where artificial tissues can be implanted to restore, repair, and improve the function of failing natural organs, are as enormous as the challenges are daunting. Progress will hinge on new research in two areas: developmental biology and biomaterials engineering. The research proposed here seeks a nonconventional approach that integrates molecular-genetic information from developmental biology with engineering knowledge of the mechanics of epithelial tissues. This integration is motivated by the fact that biological tissues grow not only according to a genetic blueprint, but also subject to the mechanical forces and deformation in their physical environment. Mechanically, soft tissues often behave in ways that resemble complex fluids and soft solids. The central idea of this proposal is to translate computational methods developed for complex fluids and soft matter to a novel class of problems in the dynamics and growth of epithelial issues. Epithelium refers to the skin that encloses organs and embryos. It is also the key structure that folds during early development of embryos to form internal organs. Toward a quantitative understanding of such processes, we develop a mathematical model that bridges the cellular scale and the much larger tissue scale. A crucial feature of the model is to properly capture the information exchange between the two scales. For example, sustained stress on a skin tissue tends to trigger structural changes in polymers that form the skeleton of each cell, and to dissolve the adhesive connection among neighboring cells. Thus the whole tissue can deform or “flow”. In return, small-scale biochemistry inside a cell produces signaling proteins that control cell division and death, and these events ultimately feed back to the overall behavior of the tissue on the large scale. We further carry out computer simulations of various scenarios of tissue growth, adapting an extensive numerical toolkit that we have developed for the dynamics of complex fluids, interfaces and soft membranes. In scientific terms, we expect two major outcomes from this research. The first is to lay the foundation for a quantitative understanding of epithelium dynamics. In particular, we wish to clarify how mechanical forcing and deformation change the properties of a tissue and affect its ability to grow under laboratory conditions. The second is to develop the ability to solve “inverse problems” in tissue engineering. That is the ability to prescribe optimal experimental conditions and protocols that will produce the desired morphology for a tissue or organ. Such outcomes will be major advances toward the goal of custom-designed artificial organs, with far-reaching health-care benefits for Canada and beyond. A less tangible but equally important benefit of the research will be the specialized training of young scientists in this emerging field. They will be exposed to cutting edge, interdisciplinary research that uses physics and engineering tools to study biology and to inform medicine. This will prepare them for the expanding frontiers of Research and Development in the decades to come.