PDF(Pubmed)
Abstract：
Biophysical factors play a fundamental role in human embryonic development. Traditional in vitro models of organogenesis focused on the biochemical environment and did not consider the effects of mechanical forces on developing tissue. While most human tissue has a Young\'s modulus in the low kilopascal range, the standard cell culture substrate, plasma-treated polystyrene, has a Young\'s modulus of 3 gigapascals, making it 10,000-100,000 times stiffer than native tissues. Modern in vitro approaches attempt to recapitulate the biophysical niche of native organs and have yielded more clinically relevant models of human tissues. Since Clevers\' conception of intestinal organoids in 2009, the field has expanded rapidly, generating stem-cell derived structures, which are transcriptionally similar to fetal tissues, for nearly every organ system in the human body. For this reason, we conjecture that organoids will make their first clinical impact in fetal regenerative medicine as the structures generated ex vivo will better match native fetal tissues. Moreover, autologously sourced transplanted tissues would be able to grow with the developing embryo in a dynamic, fetal environment. As organoid technologies evolve, the resultant tissues will approach the structure and function of adult human organs and may help bridge the gap between preclinical drug candidates and clinically approved therapeutics. In this review, we discuss roles of tissue stiffness, viscoelasticity, and shear forces in organ formation and disease development, suggesting that these physical parameters should be further integrated into organoid models to improve their physiological relevance and therapeutic applicability. It also points to the mechanotransductive Hippo-YAP/TAZ signaling pathway as a key player in the interplay between extracellular matrix stiffness, cellular mechanics, and biochemical pathways. We conclude by highlighting how frontiers in physics can be applied to biology, for example, how quantum entanglement may be applied to better predict spontaneous DNA mutations. In the future, contemporary physical theories may be leveraged to better understand seemingly stochastic events during organogenesis.
摘要：
生物物理因素在人类胚胎发育中起着重要作用。传统的器官发生体外模型侧重于生化环境，没有考虑机械力对发育组织的影响。虽然大多数人体组织的杨氏模量在低千帕范围内，标准细胞培养基质，经等离子体处理的聚苯乙烯,杨氏模量为3吉帕斯卡，使它比天然组织硬10,000-100,000倍。现代体外方法试图概括天然器官的生物物理生态位，并产生了更多临床相关的人体组织模型。自从Clevers\'2009年肠道类器官概念以来，该领域迅速扩展，产生干细胞衍生结构，转录上类似于胎儿组织，人体几乎每个器官系统。出于这个原因,我们推测，类器官将在胎儿再生医学中产生首次临床影响，因为离体产生的结构将更好地匹配天然胎儿组织。此外，自体来源的移植组织将能够与发育中的胚胎一起动态地生长，胎儿环境.随着类器官技术的发展，由此产生的组织将接近成人器官的结构和功能，并可能有助于弥合临床前候选药物和临床批准的治疗药物之间的差距。在这次审查中,我们讨论了组织硬度的作用，粘弹性,器官形成和疾病发展中的剪切力，建议将这些物理参数进一步整合到类器官模型中，以改善其生理相关性和治疗适用性。它还指出，机械传导性Hippo-YAP/TAZ信号通路是细胞外基质硬度之间相互作用的关键参与者，细胞力学，和生化途径。最后，我们强调了物理学的前沿如何应用于生物学，例如,如何应用量子纠缠来更好地预测自发的DNA突变。在未来,可以利用当代物理理论来更好地理解器官发生过程中看似随机的事件。
