破而后立：断裂如何塑造组织与器官
内容总结：
“破而后立”：科学家揭示生物组织如何通过“可控破裂”塑造器官
在生命孕育的最初阶段，一个看似“破坏性”的物理过程，正扮演着至关重要的“建设者”角色。近期，一项跨学科研究揭示，从早期胚胎到跳动的心脏，许多器官的形成并非仅由基因指令完成，而是依赖于一种精密的“可控破裂”机制。
胚胎的“爆破”成形
以小鼠胚胎为例。在植入子宫壁前，原本紧密的细胞团会经历一场戏剧性变化：细胞间涌现出数百个充满液体的小泡。这些小泡不断膨胀，挤压细胞膜，最终在精确控制的力学作用下“撬开”细胞间的连接。随后，小泡融合成单一腔室（囊胚腔），使胚胎转变为中空的囊胚结构，为后续发育奠定基础。
法国法兰西学院的物理学家埃尔韦·蒂利耶及其合作者指出，这种“破裂”与传统认知中材料随机断裂截然不同。它受细胞间物理张力和连接强度的严格调控，且破裂是暂时的——细胞在几小时内会重新密封连接。这种机制高效地重塑了组织形态。
心脏的“力学锻造”
这种“建设性破裂”在器官形成中更为普遍。以斑马鱼心脏为例，其心室内壁的肌小梁（增强泵血能力的关键结构）的形成，就源于物理力的“雕刻”。
伦敦弗朗西斯·克里克研究所的发育生物学家拉什米·普里亚团队发现，在心脏开始跳动后，其外 curvature（弯曲处）的“心脏胶质”（一种蛋白质支架）因承受巨大的周期性拉伸力而出现微裂纹。心肌细胞感知到这些裂纹后，会迁移进入其中，并以此为“种子”生长出肌小梁网络。通过改变心率或心脏形状，研究团队证实了这一过程完全由力学应变驱动，而非特定基因的局部表达。
普遍存在的塑造工具
今年2月发表于《发育》期刊的一篇综述论文汇总了多个案例，表明从斑马鱼鼻孔、水螅口部到果蝇腿部，这种“可控破裂”机制在动物界广泛存在。尽管具体机制因组织和物种而异，但它显然是一种高效且反直觉的形态发生策略。
日内瓦大学理论生物学家米歇尔·米林科维奇评论道，力学机制为理解进化多样性提供了新视角：组织特性的微小调整，通过褶皱、弯曲、破裂等物理过程，就能产生形态各异的复杂结构。
跨学科揭开生命奥秘
这一认知的突破，得益于物理学家与生物学家的紧密合作，以及高分辨率成像、力学测量和计算机模拟等技术的进步。西班牙加泰罗尼亚理工大学理论物理学家马里诺·阿罗约强调，生命组织充满流体、能动态自重建并响应力学信号，远比传统惰性材料复杂，因此必须对经典力学理论进行“生物适配”。
如今，研究人员正主动寻找更多“建设性破裂”的例证。正如普里亚所说：“在生物学中，破裂并不总意味着失败。它常常是构建新事物的必要步骤。” 这项研究不仅革新了我们对生命形态塑造的理解，也为生物力学和再生医学开辟了新的思路。
中文翻译：
破而后立：断裂如何塑造组织与器官
让-莱昂·梅特尔
就在那团紧密的细胞团——即发育中的小鼠胚胎——准备植入子宫的前一刻，它突然分崩离析。
在这个仅有几十个细胞的球体中，数百个微小的充液气泡在细胞间膨胀。气泡不断扩张，向外挤压细胞膜——随后在断裂的瞬间将细胞强行分开。分离的胚胎漂浮着，纤细的蛋白质支柱将细胞松散相连。几小时内，小气泡逐渐汇入大气泡，直至液体融合成单一空腔。凭借这一决定性特征，受精卵发育成囊胚，准备嵌入子宫内膜。在这个经断裂重塑的中空细胞球内部，胎儿将开始生长。
“这是断裂，但并非你想象的那种方式，”法国法兰西公学院的物理学家埃尔韦·蒂利耶解释道。他是揭示小鼠胚胎这一过程的团队成员之一。通常，断裂是应力作用下在惰性材料（如冰、岩石或混凝土）中随机扩展的裂纹。但蒂利耶团队在小鼠胚胎中观察到的断裂展现出不同特性：它们通过严格受控的机械过程产生，由物理张力差异和细胞间连接强度调控；断裂仅是暂时的——分裂几小时后细胞会重新闭合；且这些断裂具有建设性，能从发育组织中塑造新形态。科学家们发现，这种进化策略遍布动物界。
塑造组织需要力学作用——对于长期使用显微镜的物理学家而言，这与生物学家的认知同样明显。从生命最初时刻开始，增殖的细胞被挤压、拉伸、牵引，形成弯曲扭转的组织，进而发育成扩张收缩的器官。“这一切显然涉及大量力学过程，”瑞士日内瓦大学理论生物学家米歇尔·米林科维奇表示，他曾观察到非洲象皮肤形成过程中的机械断裂现象。
当物理学家涉足生物学时，他们的第一反应通常是套用力学理论，“直接应用”于生物系统，西班牙加泰罗尼亚理工大学理论物理学家马里诺·阿罗约指出。但活细胞和组织远比物理学家通常研究的无生命材料更奇特、更动态：它们充满液体，持续自我重建，并对复杂的化学信号与机械力混合作用产生主动响应。“必须彻底改造这些理论，”阿罗约强调，“因为活体组织在许多方面截然不同。”
过去几十年间，得益于能高分辨率成像细胞、测量力并操控组织的新型精密仪器与先进技术，力学生物学（研究细胞和组织中物理力的学科）得以复兴。然而，关于某些生长组织如何通过主动断裂形成新功能形态的发现，仍是近期惊喜。生物学家和物理学家团队运用定制工具与融合材料科学数十年理论的计算机模型，正在破译其中的作用机制，证明那些看似破坏性的力量对某些器官的形成至关重要。
今年2月发表于《发育》期刊的综述论文，汇集了生命树各生物发育组织中建设性断裂的案例。尽管不同组织和生物的基础机制可能各异，但这些过程的普遍存在表明：断裂是一种塑造组织及其关键特征的有效方式（即便有违直觉），同时揭示了进化的新机制。
“在生物学中，断裂并非总是失败，”论文合著者、伦敦弗朗西斯·克里克研究所发育生物学家拉什米·普里亚指出。她曾观察斑马鱼心脏发育中的裂纹形成。“它常是构建新事物的必要步骤。”
组织压裂
早在蒂利耶团队发现液体如何裂解数日龄小鼠胚胎之前，研究人员已猜测加压流体流动产生的力（即液压）可能是活组织自我重塑的途径之一。
2015年，为模拟上皮组织断裂，巴塞罗那科学家在充液凝胶上培养单层细胞。令人惊讶的是，当他们拉伸凝胶牵拉细胞层时，组织并未破裂；仅在释放张力让凝胶回缩时断裂才发生。由阿罗约和加泰罗尼亚生物工程研究所物理学家泽维尔·特雷帕特领导的团队意识到，充液水凝胶如同被挤压的海绵：收缩时排出水分，水流以巨大压力侵入细胞间隙导致细胞层破裂。
由于活组织细胞像水凝胶一样充满水分，物理学家“推测这种液压断裂可能在生物学中发挥作用，”阿罗约回忆道，但团队未深入探究该设想。
2019年，蒂利耶与其合作者、巴黎居里研究所细胞与发育生物物理学家让-莱昂·梅特尔，在活体组织（培养皿中生长的小鼠受精卵）中观察到类似断裂过程。研究人员以每分钟一次的频率成像（远超以往速度），从受精卵即将附着子宫壁的阶段开始记录。蒂利耶观察到，充液气泡在细胞间膨胀后又收缩。
他立即联想到奥斯特瓦尔德熟化过程——许多小颗粒、气泡或液滴合并成较少较大个体的现象。这种自发过程是泡沫浴随时间消泡的主因：压力差驱使空气从小气泡扩散至大气泡。类似地，在小鼠胚胎中，细胞间小气泡随着所含液体沿压力梯度流动而让位于大气泡，直至仅剩单个大空腔（囊胚腔）。
“这是我在软物质物理中反复观察到的现象，”蒂利耶说，“我花了两分钟意识到这种类比。”梅特尔团队又耗时一年通过实验证明该过程如何将小鼠受精卵细胞球重塑为中空球体——囊胚。
二人从先前研究中得知，小鼠胚胎中某些细胞因内部支架（支撑细胞膜并保持紧绷）差异而比其他细胞更紧绷坚固。新测量显示，当液体涌入细胞间隙在细胞膜形成凹陷时，气泡主要向较弱细胞凸出。
为测试这些差异是否影响囊胚腔形成，梅特尔实验室混合紧绷细胞与较弱细胞构建嵌合小鼠受精卵，观察其发育为囊胚的过程。这是胚胎发育的关键阶段，因为囊胚腔最终的偏心位置决定了小鼠背腹对称轴。无论如何，空腔总在较弱细胞旁形成；换言之，水流沿阻力最小路径前进。“液体流向……细胞变形更快的区域，”蒂利耶解释。他们的模拟实验得出相同结论。
基因可能编码细胞张力的初始差异，但物理机制迅速接管。“力学过程展开太快，基因组来不及发挥作用，”梅特尔说。当液体在细胞间涌出时，会压缩受精卵中所有较弱细胞并断裂其与邻近细胞的连接。在物理力支配下，发育中的胚胎似乎“别无选择”，只能将囊胚腔置于一侧，“这机制极其稳定，”蒂利耶强调。
对漂浮子宫中的受精卵而言，断裂众多细胞连接看似毁灭性。但阿罗约指出，由于每个细胞间出现许多微小裂纹，单一灾难性断裂不会撕裂胚胎。数日龄小鼠胚胎揭示的机制“表明像我们这样的哺乳动物正是在此刻通过断裂细胞连接构建而成。”
蒂利耶和梅特尔的小鼠胚胎研究确立了裂纹可塑造生物体的观念。几年后，对发育心脏的密切观察“极大拓展了断裂作为形态发生机制的理念，”阿罗约表示——这是一种能构建柔韧耐用组织器官的机制。
心脏破局者
活组织能承受巨大力量，但没有器官如心脏般充满活力与力量。它是脊椎动物发育中首个形成的器官，且立即投入工作：在尚未完全成形、仍为直管状时便开始搏动。斑马鱼心脏每分钟搏动约150次（每秒2.5次），随节律脉动扩张近两倍体积后收缩。“试想工程师要构建承受如此机械变形的结构，这简直疯狂，”巴塞罗那欧洲分子生物学实验室理论计算物理学家亚历杭德罗·托雷斯-桑切斯感叹。
心脏的力量依赖小梁——衬于心室内壁帮助泵血的肌束。没有这层活性网格，心脏将无法搏动，血液也不能流动。克里克研究所生物学家普里亚在博士后期间发现，小梁由从心壁排出的细胞受机械力作用形成。但她对现有解释（关于小梁为何起源于外曲率——即管状心脏扭转成形时的凸起部位）并不满意。
外曲率承受巨大应变：它正对血液进入心脏的瓣膜，直接承受血流冲击。研究者曾推测该区域某些基因更活跃，从而解释肌性小梁网络的形成。但当普里亚与学生克里斯托弗·陈观察时，“没有酶在正确时间或位置出现，”普里亚说。这种缺失让研究者转向基因指令之外的另一种可能：物理学。
普里亚与陈对斑马鱼心脏形成过程成像，以每秒高达100帧的不同间隔捕捉其形状变化。心脏开始搏动仅六小时后，他们注意到外曲率心胶质（支撑心脏组织的蛋白质固体网络）出现显著裂隙。这些裂隙如断裂般扩散，出现一天后，小梁肌束开始跨越裂隙编织。此时序暗示裂隙可能与小梁形成有关。
他们邀请托雷斯-桑切斯团队的计算科学家丹尼尔·桑托斯-奥利万开发心脏搏动模拟，结果显示心胶质裂隙确属断裂。模型表明，随着心脏脉动成形，应变集中于外曲率，大幅拉伸收缩胶质支架致其变薄、弱化最终破裂。外曲率心肌细胞感知这些断裂后从心壁剥离，落入胶质新生裂隙中萌发小梁。没有模拟实验，“我们永远无法想到这过程受几何控制，”普里亚坦言。
为验证假设，研究者加速斑马鱼心率；心胶质产生更多断裂。减慢心率时，裂纹减少。这证实断裂是依赖心脏收缩巨大应变的物理过程。另一验证实验中，团队培育出直管状心脏；此时断裂方向也随之改变。该行为是“断裂的典型特征，”托雷斯-桑切斯说，“让我们确信观察到的正是断裂现象。”
普里亚团队随后在鸡胚心脏中也观察到类似断裂。基于这些初步发现，“可以推测人类心脏可能由类似结构过程塑造，”她表示。无论如何，他们正在接受同行评审的斑马鱼研究表明，关键器官的基本特征由机械力先于遗传因素塑造。
断裂可作为发育过程中建设性工具的新发现，并不意味着该现象特别普遍。但它确实广泛存在于动物界：已知破裂、撕裂和裂纹塑造了斑马鱼鼻孔、水螅口部、果蝇腿部和整个扁虫形体。然而由于断裂看似极具破坏性，几乎与生长背道而驰，直到近期才被确认为组织塑造方式——普里亚、托雷斯-桑切斯、桑托斯-奥利万与陈合著的综述论文系统总结了这一认知。
梅特尔推测，随着研究者开始主动寻找，更多断裂案例将被发现。近年来，科学家已发现除断裂外，活组织还通过物理机制产生褶皱、弯曲、皱纹和折叠，仅需对组织特性与结构稍加调整就能产生惊人多样性。“这影响深远，”米林科维奇评价，“力学让进化更易理解。”
英文来源：
Break It To Make It: How Fracturing Sculpts Tissues and Organs
Jean-Léon Maître
There’s a moment, just before the tight mass of cells that is a developing mouse embryo implants itself in the womb, that it all comes apart.
Hundreds of tiny fluid-filled bubbles expand between each of the orb’s few dozen cells. The bubbles grow and press outward on cell membranes — and then, in a moment of fracture, pry them apart. Thin protein stands tether the cells together as the dissociated embryo floats. Over the course of a few hours, the smaller bubbles empty into larger ones, until the fluid coalesces into a single cavity. With this defining feature, the zygote becomes a blastocyst, ready to embed itself in the lining of the uterus. And inside this hollow ball of cells, reshaped by fracture, a fetus will grow.
“It’s fracturing, but not in a way like you might imagine,” said Hervé Turlier, a physicist at the Collège de France in Paris and a member of the team that characterized this process in mouse embryos. Typically, fractures are fault lines that propagate haphazardly under stress and spread through inert materials, such as ice, rock, or concrete. But the fractures that Turlier’s colleagues observed in mouse embryos display different characteristics. They emerged via a tightly controlled mechanical process, governed by differences in physical tension and cells’ bonds to one another. The fractures were also only temporary: Within hours of splitting, the cells sealed back together again. And these fractures were constructive, sculpting new shapes from developing tissues, in an evolutionary approach that scientists are uncovering across the animal kingdom.
Shaping tissues requires forces — that much has been obvious to the physicists who have peered down microscopes for almost as long as biologists have. From life’s first moments, multiplying cells are squished, stretched, and tugged to form tissues that bend and twist into organs that expand and contract. “All that is obviously involving a lot of mechanics,” said Michel Milinkovitch, a theoretical biologist at the University of Geneva in Switzerland who has observed mechanical fracturing during the formation of African elephant skin.
Patrick Imbert, Collège de France; Mathieu Baumer
When physicists approach biology, their first instinct is usually to take a theory about mechanics “and just apply it” to a biological system, said Marino Arroyo, a theoretical physicist at the Polytechnic University of Catalonia in Spain. But living cells and tissues are far stranger and more dynamic than the lifeless materials physicists typically study. They are filled with fluid, continually rebuild themselves, and actively respond to a complex mix of chemical signals and mechanical forces. “You have to really adapt these theories,” Arroyo said, “because living tissues are very different in many ways.”
Over the past decades, thanks to new precision instruments and advanced techniques that can image cells at high resolution, measure forces, and manipulate tissues, there has been a resurgence in mechanobiology, the study of physical forces in cells and tissues. However, the discovery of how some growing tissues deliberately fracture themselves to make new functional shapes has been a recent surprise. Using custom-built tools and computer models that incorporate decades-old theories from materials science, teams of biologists and physicists are deciphering the mechanisms at play and demonstrating that forces that seem destructive are essential to how some organs form.
A review paper, published in Development in February, compiles examples of constructive fractures in developing tissues of organisms across the tree of life. Although the underlying mechanisms may differ from tissue to tissue, and from organism to organism, the apparent ubiquity of these processes suggests that fracturing is a useful, if counterintuitive, way to sculpt tissues and their vital features. It’s also revealing new machinations of evolution.
“In biology, breaking isn’t always a failure,” said review co-author Rashmi Priya, a developmental biologist at the Francis Crick Institute in London who has watched cracks form in developing zebra fish hearts. “It’s often a necessary step in building something new.”
Tissue Fracking
Years before Turlier and his collaborators discovered how fluid cracks apart a days-old mouse embryo, researchers had a hunch that forces from the flow of pressurized fluids, also known as hydraulics, might be one way living tissues reshape themselves.
In 2015, to model fractures in epithelial tissues, scientists in Barcelona grew a single layer of cells on top of a fluid-filled gel. To their surprise, when they stretched the cell layer by pulling on the gel, it didn’t break apart; that happened only when they released the tension and let the gel relax. The team, led by Arroyo and the physicist Xavier Trepat at the Institute for Bioengineering of Catalonia, realized that the fluid-filled hydrogel behaved like a squeezed sponge: As it contracted, it expelled its water, which pushed between the cells with so much force that the cell layer ruptured.
Since cells of living tissues are brimming with water, just like hydrogels, the physicists “speculated that this hydraulic fracture could play a role in biology,” Arroyo recalled. But they didn’t pursue the idea further.
In 2019, Turlier and his collaborator Jean-Léon Maître, a cell and developmental biophysicist at the Curie Institute in Paris, observed a similar fracturing process in living tissue — mouse zygotes growing in a dish. The researchers imaged them once a minute, much faster than scientists ever had before, starting at the stage just before the zygotes would normally adhere to the womb wall. As Turlier watched, the fluid-filled bubbles ballooned between cells and then shrunk.
He immediately saw similarities to a process known as Ostwald ripening, in which many small particles, bubbles, or droplets join into fewer larger ones. This spontaneous process is the main reason why bubble baths lose their foam over time: Driven by pressure differences, air diffuses from smaller bubbles into larger ones. Similarly, in the mouse embryo, small bubbles between cells give way to large bubbles as the fluid they contain flows along pressure gradients, until only one large cavity, the blastocoel, remains.
“This is something I’ve seen over and over in soft matter physics,” Turlier said. “It took me two minutes to realize the analogy.” It took Maître’s team another year to show experimentally how the process reshapes the ball of cells that is a mouse zygote into a hollow sphere, the blastocyst.
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The duo knew from their previous studies that certain cells in the mouse embryo were tenser and sturdier than others due to differences in their internal scaffolds, which underpin the cell membrane and keep it taut. Taking new measurements, the researchers saw that as fluid gushed between cells, creating indentations in their cell membranes, bubbles mostly bulged into weaker cells.
To test whether those differences affected the formation of the blastocoel, Maître’s lab mixed tenser cells with weaker ones to form chimera mouse zygotes. Then they watched the zygotes become blastocysts. This is a crucial stage of embryonic development, as the final, off-center position of the blastocoel sets the axis of symmetry for the mouse’s back and belly. No matter what, the cavity always formed adjacent to the weaker cells; in other words, the water flowed along the path of least resistance. “The fluid goes … where [cells] deform faster,” Turlier said. Their simulations produced the same result.
Genes might program the initial differences in cells’ tension, but then physics quickly takes over. The mechanics unfold “too fast for the genome to play a role,” Maître said. As fluid bubbles up between cells, it compresses any weaker cells in the zygote and fractures their connections with neighboring cells. Governed by physical forces, the growing embryo seems to have “no other choice” than to put its blastocoel to one side, Turlier said. “It’s extremely robust.”
Breaking so many contacts between cells may seem ruinous for a zygote floating in the womb. But because many small cracks appear between every cell, a single, catastrophic fracture doesn’t rip the embryo open, Arroyo said. The mechanism revealed in days-old mouse embryos “showed that mammals like us are built at [this] moment by fracturing cell-cell junctions,” he said.
Turlier and Maître’s studies of mouse embryos established the idea that cracks can shape organisms. A few years later, close observation of the developing heart would “greatly expand the idea of fracture as a morphogenetic mechanism,” Arroyo said — one that can build pliable and durable tissues and organs.
Heart Breaker
Living tissues can withstand immense forces, but no organ is quite as lively or forceful as the heart. It’s the first organ to form in vertebrate development, and it gets straight to work: beating before it’s fully formed, while it’s still a straight, deflated tube. The zebra fish heart beats about 150 times per minute — or 2.5 times per second — and expands to nearly twice its size and then contracts with each rhythmic pulse. “Just imagine from the viewpoint of an engineer trying to generate a structure that is undergoing such mechanical deformations. I mean, it’s crazy,” said Alejandro Torres-Sánchez, a theoretical computational physicist at the European Molecular Biology Laboratory in Barcelona.
Its force depends on trabeculae, muscular strands that line the heart’s inner walls to help it pump. Without this active mesh, the heart would not beat, and blood would not flow. During her postdoc, Priya, the Crick Institute biologist, discovered that trabeculae are created by mechanical forces that expel cells from the heart wall. But she wasn’t satisfied with existing explanations for why trabeculae originate in the outer curvature, a bulge that forms as the tubular heart twists into shape.
The outer curvature endures great strain: Located directly opposite the valve through which blood enters the heart, it gets hit with incoming blood. Researchers presumed that certain genes were more active in this part of the heart, and that this activity explained the formation of the muscular network of trabeculae. But when Priya and her student Christopher Chan looked, “none of the enzymes were there in the right time [or the] right place,” Priya said. Their absence left the researchers with one alternative to genetic instructions: physics.
Priya and Chan imaged zebra fish hearts as they formed, capturing up to 100 frames per second at various intervals to closely follow any changes in their shape. Just six hours after the heart started beating, they noticed prominent gaps in the outer curvature’s cardiac jelly, a solid network of proteins that props up heart tissue. These gaps spread like fractures, and one day after they appeared, trabeculae strands started to knit their way across them. That timing suggested that these gaps might have something to do with how trabeculae form.
They asked the computational scientist Daniel Santos-Oliván on Torres-Sánchez’s team to develop simulations of beating hearts, which revealed that the gaps in the cardiac jelly were indeed fractures. The model showed that as the heart pulses and takes shape, strain concentrates in the outer curvature, stretching and contracting the jelly scaffold so much that it thins, weakens, and eventually breaks. Sensing those fractures, heart muscle cells at the outer curvature then peel away from the heart wall and fall into the jelly’s newly formed cracks, where they seed the trabeculae. Without the simulations, “we could never have thought that [this process] is controlled by geometry,” Priya said.
Courtesy of Rashmi Priya
To test that hypothesis, the researchers sped up the zebra fishes’ heart rate; more fractures formed in the cardiac jelly. When they slowed the hearts, fewer cracks appeared. This confirmed that the fracturing was a physical process dependent on the incredible strain of heart contractions. To test it another way, the team engineered hearts to grow straight and tubular; when they did so, the fractures changed their direction, too. That behavior is “characteristic of a fracture,” Torres-Sánchez said, and “made us sure that these were [fractures] we were looking at.”
Priya’s team has since seen these fractures in the hearts of chicken embryos. Based on these preliminary findings, “it is tempting to speculate that human hearts might be shaped by similar structural processes,” she said. In any case, their zebra fish work, which is undergoing peer review, shows that a fundamental feature of an essential organ is shaped by mechanical forces ahead of genetics.
The recent revelation that fracturing can be a constructive tool during development doesn’t mean the phenomenon is particularly common. Still, it is widespread in animals: Ruptures, tears, and cracks are known to shape zebra fish nostrils, hydra mouths, fruit fly legs, and whole flatworms. And yet because fracturing seems so destructive, almost antithetical to growth, it has only recently been recognized as a way of shaping tissues, summed up in the recent review paper co-authored by Priya, Torres-Sánchez, Santos-Oliván, and Chan.
Maître suspects that more examples of fracturing will be found now that researchers know to look for it. In recent years, researchers have discovered that, aside from fracturing, living tissues also crumple, buckle, wrinkle, and fold via physical mechanisms that produce incredible diversity with just a few slight tweaks in tissue properties and architecture. “This is really far-reaching,” Milinkovitch said. Mechanics makes evolution “much easier to understand.”